Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][S:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:12][O:13][C:9]=2[C:8]=1[Cl:23])[CH3:2].OO.C(O)=[O:28].C(Cl)Cl>O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][S:6]([C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:12][O:13][C:9]=2[C:8]=1[Cl:23])=[O:28])[CH3:2]
Reactant: O=CO
Reactant: CCOC(=O)CSc1ccc2c(-c3ccccc3F)noc2c1Cl
Agent: OO
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CS(=O)c1ccc2c(-c3ccccc3F)noc2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.0g (8.2 mmole) of ethyl[[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]thio]acetate, 2.5g of a 30% H2O2 solution, 10 ml of formic acid and 50 ml of CH2Cl2 was stirred at room temperature for two hours. The reaction was diluted with water and extracted three times with CH2Cl2. The organics were combined, washed with dilute NaHCO3 and dried over MgSO4. The solution was concentrated at reduced pressure to a yellow oil which solidified to a cream-colored solid, 3.0g (94%) of ethyl[[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]sulfinyl]acetate, m.p. 115°-118° C. The solid was recrystallized from ether to afford pale yellow prisms of ethyl[[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]sulfinyl]acetate, m.p. 120°-121° C.
Reaction SMILES: [Li+].[B-](CC)(CC)CC.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20]3[CH:21]=[C:22]4[C@:27]([C:29](OC)=[O:30])([CH2:28][C:19]=3[CH:18]=[N:17]2)[CH2:26][N:25]([S:33]([C:36]2[CH:37]=[C:38]([CH3:42])[CH:39]=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH2:24][CH2:23]4)=[CH:12][CH:11]=1>O1CCCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20]3[CH:21]=[C:22]4[C@:27]([CH2:29][OH:30])([CH2:28][C:19]=3[CH:18]=[N:17]2)[CH2:26][N:25]([S:33]([C:36]2[CH:37]=[C:38]([CH3:42])[CH:39]=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH2:24][CH2:23]4)=[CH:12][CH:11]=1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cccc(C)c1)C2
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(CO)C2)c1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
Superhydride (1M solution in tetrahydrofuran, 43.2 ml, 43.2 mmol) was added slowly to a solution of (R)-methyl 1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (5.2 g, 10.80 mmol) in tetrahydrofuran (100 mL) at 0° C. and stirred for 2 hours. The reaction was quenched with ammonium chloride solution (aqueous, 100 mL) and ethyl acetate (100 mL) was added. The phases were separated and the organic phase was washed with brine (100 mL), dried (sodium sulphate) and solvent removed to give a yellow oil. The crude product was purified by chromatography on silica gel (gradient: 0-80% ethyl acetate in isohexane) to afford (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol (4.45 g) as a white solid. LCMS (Method F, ES-API): RT 2.36 min, m+H=454.
Reaction SMILES: [Cl-].[NH4+].C(O)(=O)C.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[CH2:16][Cl:17])=[C:10]([N+:19]([O-])=O)[CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C=O)C>[NH2:19][C:10]1[CH:9]=[C:8]([Br:7])[CH:13]=[CH:12][C:11]=1[NH:14][C:15](=[O:18])[CH2:16][Cl:17]
Reactant: O=C(CCl)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Br)ccc1NC(=O)CCl
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 43.3 %

Procedure:
Ferrous powder (19.8 g, 354 mmol), ammonium chloride (1.1 g, 19.7 mmol) and acetic acid (4.9 ml, 86.5 mmol) were suspended in 300 ml water and stirred at 50° C. for 15 min. To this mixture, a solution of N-(4-bromo-2-nitrophenyl)-2-chloroacetamide (11.5 g, 39.3 mmol) in 100 ml DMF was added quickly. After stirring for 15 min, the mixture was basified to pH 9 with aqueous sodium carbonate solution. The remaining solids were filtered and washed with water and ethyl acetate. Extraction of the water layer with ethyl acetate, washing of the combined organic layers with brine, drying over MgSO4, removing the solvent under reduced pressure and purification of the crude product by flash chromatography on silica gel (petroleum ether/ethyl acetate, 1/1) yielded N-(2-amino-4-bromophenyl)-2-chloroacetamide (4.5 g, 17.0 mmol, 43%) as an off-white solid.
Reaction SMILES: [OH:1][CH:2]([C:17]([F:20])([F:19])[F:18])[CH2:3][CH:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:6]=2[O:5]1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:22]1([CH2:21][O:1][CH:2]([C:17]([F:20])([F:18])[F:19])[CH2:3][CH:4]2[CH2:9][CH2:8][C:7]3[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:6]=3[O:5]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCC(CC(O)C(F)(F)F)O2
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)CCC(CC(OCc1ccccc1)C(F)(F)F)O2

Procedure:
A solution of 5.0 g (17 mmol) of 2-(2-hydroxy-3,3,3-trifluoropropyl)-6-nitro-3,4-dihydro-2H-1-benzopyran in a mixture of 60 ml of toluene and 20 ml of dichloromethane is stirred for 3 hours with 6.1 ml (52 mmol) of benzyl bromide, 0.55 g (1.7 mmol) of tetrabutylammonium bromide and a solution of 2.7 g (69 mmol) of sodium hydroxide in 5.4 ml of water. The reaction mixture is then diluted with dichloromethane and washed with water, then the organic phase is dried over sodium sulfate and concentrated under reduced pressure. By chromatography of the residue on a silica column using cyclohexane containing 0 to 50% of dichloromethane, 5.9 g of product are obtained.
Reaction SMILES: C[O:2][C:3](=[O:15])[C@@H:4]([OH:14])[C@@H:5]([CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([O:8]C)=[O:7].[OH-].[Na+].Cl>CO.O>[CH2:10]([C@@H:5]([C:6]([OH:8])=[O:7])[C@H:4]([OH:14])[C:3]([OH:15])=[O:2])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[C@@H](C(=O)OC)[C@H](O)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC[C@@H](C(=O)O)[C@H](O)C(=O)O
Reaction time: 24 h

Procedure:
To (2S,3R)-3-(n-butyl)-2-hydroxysuccinic dimethyl ester B-3 in MeOH (28 mL) is added a solution of NaOH (2.2 g, 55 mmol) in water (28 mL). After 24 hours, the MeOH is removed, the crude reaction is acidified with HCl (6 N, 12 mL) to pH=1, and then extracted with EtOAc (3×50 mL). The combined organic layers are dried (Na2SO4) and concentrated to give (2S,3R)-3-(n-butyl)-2-hydroxysuccinic acid B-4.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].C(OC([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]=O)[CH2:31][CH2:30]1)=O)(C)(C)C.[B-][N+](C)(C)C>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:14]=[CH:15][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:17][C:2]=2[NH:1][CH2:35][CH:32]2[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]2)=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(N)c1
Agent: [B-][N+](C)(C)C
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NCC2CCNCC2)c1
Yield: 83.2 %

Procedure:
Using a similar procedure to that described in Example 47-C&D, 2-amino-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamide (1.00 g, 3.28 mmol), 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (1.05 g, 4.92 mmol), and borane trimethylamine complex (717 mg, 9.94 mmol) afforded 1.10 g (84%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(Cl)nc2)CC1

Procedure:
The title compound was prepared from 5-bromo-2-chloropyridine and 1-methylpiperazine according to Method BG and was isolated as a brown oil (27%). LCMS (ES+) 212.0 (M+H)+, RT 1.97 minutes (70% purity) (Method 2).
Reaction SMILES: [Cl-].C(N(C(C)C)CC)(C)C.[OH:11][C@@H:12]([C@H:14]1[C:35](=[O:36])[N:16]2[CH:17]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C:18](=O)[C@H:19]([CH3:20])[C@H:15]12)[CH3:13].FC(F)(F)S(O)(=O)=O.FC(F)(F)S(O)(=O)=O.[SH:53][C@@H:54]1[CH2:58][N:57]([CH3:59])[C@H:56]([C:60]([N:62]2[CH2:67][CH2:66][N:65]([CH3:68])[CH2:64][CH2:63]2)=[O:61])[CH2:55]1>C(#N)C>[CH3:68][N:65]1[CH2:66][CH2:67][N:62]([C:60]([C@@H:56]2[CH2:55][C@H:54]([S:53][C:18]3[C@H:19]([CH3:20])[C@@H:15]4[C@@H:14]([C@H:12]([OH:11])[CH3:13])[C:35](=[O:36])[N:16]4[C:17]=3[C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)=[O:23])[CH2:58][N:57]2[CH3:59])=[O:61])[CH2:63][CH2:64]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)CC1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C)CC4)N(C)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 50 %

Procedure:
540 μl of diphenylphosophoryl chloride and 470 μl of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 920 mg of 4-nitro-benzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 10 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. 1400 μl of diisopropylethylamine and a solution of 1350 mg of (2S,4S)-4-mercapto-2-(4-methyl-1-piperazinylcarbonyl)-1-methylpyrrolidine bis(trifluoromethanesulfonate) (prepared as described in Preparation 51) in 5 ml of dry acetonitrile were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 2 hours, after which it was allowed to stand overnight in a refrigerator. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was purified by chromatography through a Lobar column (Merck, LiChroprep RP-8, size B). The column was successively eluted with 65% by volume aqueous methanol and with 70% by volume aqueous methanol. Those fractions containing the title compound were combined and concentrated by evaporation under reduced pressure, to give 730 mg of the title compound, as a powder.
Reaction SMILES: BrBr.[N:3]1([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13](Br)[CH:12]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[C:40]([N:42](C)C)=O>[Zn].[C-]#N.[Zn+2].[C-]#N.[C].[Pd]>[N:3]1([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:40]#[N:42])[CH:12]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: O=C(NN1CCOCC1)c1ccc(O)c(Br)c1
Reactant: CC(=O)N(C)C
Agent: [Pd]
Agent: BrBr
Agent: [C-]#N
Product: N#Cc1cc(C(=O)NN2CCOCC2)ccc1O
Temperature: 120 °C

Procedure:
Zinc powder (78 mg, 1.2 mmol) is suspended into dimethylacetamide (5.7 mL), and thereto is added bromine (20 μl, 0.4 mmol) at room temperature under nitrogen. The mixture is stirred until the color of bromine disappears (15-25 ), and thereto are added 3-bromo-4-hydroxybenzoic acid (4-morpholinyl)amide (572 mg, 2 mmol), zinc cyanide (118 mg, 1.0 mmol), 5% palladium-carbon (170 mg, 0.08 mmol) and triphenylphosphine (84 mg, 0.32 mmol). The vacuum deaeration and the nitrogen introduction are repeated five times. The mixture is heated at 120° C. (internal temperature) for one hour, when the inversion rate is confirmed to be 99% by HPLC. After cooling to 25° C., the insoluble materials are separated by filtration to give 3-cyano-4-hydroxybenzoic acid (4-morpholinyl)amide. The yield is 453 mg (97.6%) when determined by HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Br:13])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[H-].C([Al+]CC(C)C)C(C)C.O>C1COCC1>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Br:13])=[C:4]2[C:3]=1[C:8](=[O:9])[NH:7][CH:5]2[OH:6]
Reactant: Nc1ccc(Br)c2c1C(=O)NC2=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Br)c2c1C(=O)NC2O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
3-Amino-6-bromophthalimide (3.10 g, 12.9 mmol) was dissolved in THF (240 mL), and the solution was added with diisobutylaluminiumhydride (0.94 mol/L, 68.6 mL, 64.5 mmol) by drops at −78° C. for 25 minutes, then the reaction mixture was warmed to room temperature, followed by stirring for 1.5 hours. Then, the reaction mixture was ice-cooled, added with water and filtered using Celite. The filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by slurry using chloroform to obtain 7-amino-4-bromo-3-hydroxyisoindolinone (2.26 g, yield 72%).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:51])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[C:31]([O:32][C@H:33]([CH2:35][CH:36]=C)[CH3:34])=[CH:30][CH:29]=[C:28]([F:38])[C:27]=5[F:39])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:40])[C:12]=2[C@H:41]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([O:44][CH3:45])=[O:43])[CH2:7][CH2:6]1)[CH:2]=C.C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:47]([O:46][C@@H:41]([C:12]1[C:13]([CH3:40])=[CH:14][C:15]2=[N:19][C:18]3=[CH:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:51])([O:4][CH2:1][CH:2]=[CH:36][CH2:35][C@H:33]([CH3:34])[O:32][C:31]2[CH:30]=[CH:29][C:28]([F:38])=[C:27]([F:39])[C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)[C:42]([O:44][CH3:45])=[O:43])([CH3:48])([CH3:49])[CH3:50]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5c(O[C@@H](C)CC=C)ccc(F)c5F)c4)cn23)CC1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OC/C=C\C[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1

Procedure:
Prepared in 81.0% yield from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′,3′-difluoro-6′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate. LCMS (ESI, M+1): 674.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:22]([CH:26]1[CH2:31][CH2:30][C:29](OC)(OC)[CH2:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([CH:26]1[CH2:31][CH2:30][C:29]([O:18][CH2:17][CH2:16][C:13]2[N:14]([CH3:15])[C:10]([S:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[C:11]([CH:19]([CH3:21])[CH3:20])[N:12]=2)=[CH:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: COC1(OC)CCC(C(C)(C)C)CC1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CC(C)c1nc(CCOC2=CCC(C(C)(C)C)CC2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 70 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the enol ether with 4-tert-butyl-1,1-dimethoxycyclohexane (1 g, 5 mmol) in the same manner as the example 41 to give the compound 50 (337 mg, 70%). Mp 99.5-100.5° C. PMR (CDCl3 -0.1% d5 -Py): δH0.86 (9 H, s, t-Bu), 1.24 (6 H, d, J 4.4 Hz, (CH3)2C), 3.12 (2 H, t, J 4.2 Hz, CH2 -Im), 3.12 (1 H, m, (CH3)2CH), 3.50 (3 H, s, NCH3), 3.97 (2 H, m, OCH2), 4.61 (1 H, m, =CH), 6.77 (2 H, d, J 1 Hz, arom-H), 7.09 (1 H, t-like, arom-H). Elementary analysis (for C25H34N2Ocl2S) Calcd. : C, 62.35% H, 7.12% N, 5.82% S, 6.66% Cl, 14.72% Found: C, 62.56% H, 7.13% N, 5.76% S, 6.57% Cl, 14.43%
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].CCN(C(C)C)C(C)C>CCOC(C)=O.[Pd]>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([CH:15]=[O:16])=[CH:18][CH:19]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: O=C(Cl)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=Cc1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To a flask containing A1Cl3 (534 mg, 4.0 mmol) under an N2 atmosphere was added anhydrous CH2Cl2 (0.1 M), and the drop wise addition of oxalyl chloride (523 μL, 6.0 mmol) over a 20 min period at 15° C. Next, a solution of 2,2,2-trifluoro-1-(4-phenylpiperidin-1-yl)ethanone (17) (2.0 mmol) in anhydrous CH2Cl2 (0.1 M) was added drop-wise to the initial solution over a 45 min period at 15° C. When the reaction was complete as judged by TLC, ice was added to the solution in addition to CaCl2 (1.70 g). The product was extract into CH2Cl2, washed with brine and dried over anhydrous Na2SO4 before concentrating under reduced pressure to yield crude 4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzoyl chloride (18). (b) To a stirred solution of 18 (2.0 mmol) and DIPEA (697 μL, 4.0 mmol) in EtOAc (0.1 M) was added 10% Pd/C. The flask was then evacuated and filled with H2 gas and allowed to stir for 30 min. After which time the reaction contents were filtered and concentrated under reduced pressure to give crude product which was purified by silica gel column chromatography (hexanes:EtOAc, 2:1) to furnish 19 (320 mg, 59% (yield over 2 steps)) δH (400 MHz, CDCl3) 1.69-1.81 (m, 2H, CH2), 1.98-2.06 (m, 2H, CH2), 2.83-2.97 (m, 2H, CH2), 3.27 (td, J=12.8 and 2.4 Hz, 1H, CH), 4.13-4.21 (m, 1H, CH), 4.70-4.76 (m, 1H, CH2), 7.37 (d, J=8.4 Hz, 2H, CH), 7.85 (d, J=8.4 Hz, 2H, CH), 9.99 (s, 1H, CHO); LRMS (ES+) calcd for [C14H14F3NO2+Na] 308.09 found 308.19 [M+Na].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10](OCC)=[O:11])=[CH:8][CH:7]=[CH:6][N:5]2[CH:15]=1>C(Cl)(Cl)(Cl)Cl>[OH:11][CH2:10][C:9]1[C:4]2[N:5]([CH:15]=[C:2]([CH3:1])[N:3]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cccn2cc(C)nc12
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cn2cccc(CO)c2n1

Procedure:
From 2b (yield: 42%) as an oil; IR (CCl4) 2960, 1499, 1366, 1324 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3H), 4.96 (s, 2H), 6.64 (t, 1H, J=7 Hz), 7.11 (d, 1H, J=7 Hz), 7.25 (s, 1H), 7.88 (d, 1H, J=7 Hz); 13C NMR (100 MHz, CDCl3) δ 14.0, 60.8, 109.7, 111.9, 121.5, 124.1, 129.2, 142.2, 143.6; MS m/z 162 (M+, 36), 161 (100), 133 (55), 132 (46), 78 (31), 51 (16).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(CC)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
To a solution of 1-ethylpiperazine (1 g, 8.771 mmol, 1.0 eq) in DMF were added K2CO3 (3 g, 21.927 mmol, 2.5 eq.) and ethyl 2-bromoacetate (2.19 g, 13.156 mmol, 1.5 eq.). The mixture was stirred at RT for 16 h. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 76.4% yield (1.3 g).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1C=C[C:9](OC)=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15].CCO[C:20]([CH3:22])=[O:21]>C(Cl)Cl>[Br:5][C:6]1[C:7]([N+:14]([O-:16])=[O:15])=[CH:8][CH:9]=[CH:22][C:20]=1[OH:21]
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Reactant: CCOC(C)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(O)c1Br
Reaction time: 23 h
Yield: 79 %

Procedure:
BBr3 (1 M in CH2Cl2, 77 mL, 77 mmol) was added dropwise, over 1 h, to a stirred solution of 4-bromo-3-nitroanisole (5.0 g, 22 mmol) in 30 mL CH2Cl2 at -70° C. under nitrogen. The resulting deep burgundy-colored reaction was stirred overnight (23 h) and then poured onto 300 g crushed ice. EtOAc (250 mL) was added and the organic fraction washed with brine (250 mL), dried (MgSO4) and concentrated in vacuo to 5.06 g of a yellow-brown solid. Purification by column chromatography (EtOAc/hexane, gradient elution 5:95 to 15:85) afforded 3.77 g (79%) of 2-bromo-3-nitrophenol as a yellow solid: TLC (EtOAc/hesane 20:80) Rf =0.12; HPLC (Tr =12.2); 1H-NMR (CDCl3) δ 5.57 (s, 1H, --OH), δ 6.95 (dd, J=8 Hz, J=3 Hz, 1H), δ 7.36 (d, J=3 Hz, 1H), δ 7.58 (d, J=8 Hz, 1H); MS m/z (relative intensity) 218 (MH+, 100), 220 (MH+ +2.56).
Reaction SMILES: [NH:1]([C:3](=[O:14])[C@@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5])[NH2:2].[C:15](F)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([NH:2][NH:1][C:3](=[O:14])[C@@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH3:5])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(F)c1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NN
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of (S)-tert-butyl (1-hydrazinyl-1-oxopropan-2-yl)carbamate (293 mg, 1.44 mmol, 1.0 equv. in 3 ml of DCM) was added benzoyl fluoride (179 mg, 1.44 mmol in 2 ml of DCM), the reaction solution was stirred at room temperature for 50 min., the solvent was removed to yield the desired product. 1H NMR (400 MHz, CDCl3) δ 7.89-7.78 (m, 2H), 7.54 (t, J=7.4 Hz, 1H), 7.43 (t, J=7.6 Hz, 2H), 5.32 (b, 1H), 4.45 (b, 1H), 1.46 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C:5]([F:21])([F:20])[C@:6]([C:9]2[C:14]([F:15])=[CH:13][C:12]([OH:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)([CH3:8])[N:7]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1)=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])O.[Na+]>CC(C)=O.[I-].[K+]>[NH2:1][C:2]1[O:3][CH2:4][C:5]([F:20])([F:21])[C@:6]([C:9]2[C:14]([F:15])=[CH:13][C:12]([O:16][CH2:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=3)=[O:25])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)([CH3:8])[N:7]=1
Reactant: C[C@]1(c2cc([N+](=O)[O-])c(O)cc2F)N=C(N)OCC1(F)F
Reactant: O=C(CBr)c1ccc(Cl)cn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C[C@]1(c2cc([N+](=O)[O-])c(OCC(=O)c3ccc(Cl)cn3)cc2F)N=C(N)OCC1(F)F
Yield: 91.5 %

Procedure:
A dispersion of 4-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-2-nitro-phenol (intermediate F2.1) (120 mg, 393 μmol), 2-bromo-1-(5-chloropyridin-2-yl)ethanone (101 mg, 432 μmol), cesium carbonate (512 mg, 1.57 mmol), and potassium iodide (2 mg, 14.5 μmol) in acetone (5.51 ml) was stirred at room temperature for 20 hours. For the workup, the reaction mixture was poured into a saturated solution of sodium hydrogencarbonate (5 ml) and extracted with dichloromethane (2×5 ml). The combined organic layers were dried over sodium sulphate and evaporated at reduced pressure. The crude 2-[4-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-2-nitro-phenoxy]-1-(5-chloro-pyridin-2-yl)-ethanone (165 mg, 92% yield) was obtained as a red gum. MS (ISP): m/z=459.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C.CCOC(C)=O>[N:20]([C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1)=[N+:21]=[N-:22]
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-Chloro-5,6-diphenylpyrazine (45 mg, 0.17 mmol) in 500 μL DMF at room temperature under nitrogen was added sodium azide (11 mg, 0.17 mmol) and the reaction was warmed to 100° C. After stirring overnight, the reaction was cooled to room temperature, diluted with EtOAc (30 mL) and washed 4×30 mL with H2O and 1×30 mL with saturated NaCl. The organics were isolated, dried (MgSO4), filtered and concentrated to the 2-azidopyrazine, which exists as a yellow solid (45 mg, quantitative). 1H-NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 7.58-7.42 (m, 6H), 7.36-7.23 (m, 4H).