Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[F:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCCl>[C:25]([C:9]1[CH:8]=[N:7][N:6]2[CH:27]=[C:3]([NH:2][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[F:29])[C:4]([CH3:28])=[C:5]2[C:10]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)#[N:26]
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C(O)c1ccccc1F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1c(NC(=O)c2ccccc2F)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Yield: 41.9 %

Procedure:
6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (8 mg, 0.02 mmol), 2-fluorobenzoic acid (4.2 mg, 0.03 mmol), PyBOP (16 mg, 0.03 mmol) and DIEA (6.5 mg, 0.05 mmol) in 1,2-dichloroethane (0.5 ml) were stirred at RT for 16 hrs. The reaction mixture was concentrated and purified by silica gel flash chromatography to isolate 374 as a white solid (4 mg, 42%). [M+H]+=478.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][C@H:35]([CH3:38])[CH2:36][OH:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][C@H:35]([CH3:38])[CH2:36][OH:37])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: C[C@@H](N)CO
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@H](C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and (R)-2-amino-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H33N6O5SF2[(M+H)+] 543.2196, observed 543.2201.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[CH:12]=[C:13]([C:19]2(O[Si](C)(C)C)[CH2:21][CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>ClCCl.O>[Br:10][C:11]1[CH:12]=[C:13]([C:19]2([F:7])[CH2:21][CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C2(O[Si](C)(C)C)CC2)cc1Br
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2(F)CC2)cc1Br
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Diethylaminosulfur trifluoride (2.4 ml) was added to a solution of [1-(3-bromo-4-methoxyphenyl)cyclopropyloxy]trimethylsilane (3.84 g) in dichloromethane (68 ml). The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (1.88 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1B(O)O.[F-].[Cs+].Br[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1>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.COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1
Reactant: COC(=O)c1ccc(Br)c(OC2CCCCO2)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(OC2CCCCO2)c1
Temperature: 90 °C
Yield: 71.8 %

Procedure:
To a 2 dram vial charged with 2-fluoro-5-methoxyphenylboronic acid (available from Aldrich) (3.17 g, 18.7 mmol), tetrakis(triphenylphosphine)palladium (0) (0.719 g, 0.622 mmol), cesium fluoride (1.15 mL, 31.1 mmol), and 26.2 (1.96 g, 6.22 mmol), was added DME (20 mL). The reaction mixture was then heated at 90° C. overnight. The reaction was allowed to cool and then filtered and concentrated. The crude product was purified by combiflash (0 to 10% EtOAc/hexanes) yielding 26.3 (1.61 g, 71.8% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([N:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]4=[O:30])[CH:14]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]=3[O:17][CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[C:19]([C:15]1[C:16]([O:17][CH3:18])=[C:11]([C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:31](=[O:33])[CH3:32])[S:3][C:4]=3[CH:10]=2)[CH:12]=[C:13]([N:23]2[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]2=[O:30])[CH:14]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1c(-c2ccc3nc(N)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: CC(=O)OC(C)=O
Product: COc1c(-c2ccc3nc(NC(C)=O)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of the product from Example 83 (30 mg, 0.071 mmol) and acetic anhydride (3 mL) was stirred at 100° C. for 2 h, and then allowed to cool to room temperature. The resulting solid was collected by filtration, washed with H2O, and dried to give the title compound as an off-white solid (29 mg, 88%). 1H NMR (300 MHz, DMSO-d6) δ 12.42 (s, 1H) 11.41 (d, J=2.21 Hz, 1H) 8.12 (d, J=1.47 Hz, 1H) 7.82 (d, J=8.46 Hz, 1H) 7.78 (d, J=8.09 Hz, 1H) 7.61 (dd, J=8.46, 1.84 Hz, 1H) 7.31 (q, J=2.70 Hz, 2H) 5.64 (dd, J=8.09, 2.21 Hz, 1H) 3.24 (s, 3H) 2.22 (s, 3H) 1.41 (s, 9H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)(=[O:12])[CH3:11].[Cl:19][C:20]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:24][N:23]=[C:22]2[N:32]([CH2:41][C:42](O)=[O:43])[N:33]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]=12.Cl.CN(C)CCCN=C=NCC.OC1C=CC=C[N+]=1[O-]>C(Cl)Cl>[C:10]([N:13]1[CH2:18][CH2:17][N:16]([C:42](=[O:43])[CH2:41][N:32]2[C:22]3=[N:23][N:24]=[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]([Cl:19])=[C:21]3[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:33]2)[CH2:15][CH2:14]1)(=[O:12])[CH3:11]
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: CC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.1 %

Procedure:
A solution of diisopropylethylamine (DIPEA) (120 μL, 0.67 mmol) and 1-acetylpiperazine (38 mg, 0.3 mmol) in CH2Cl2 (1 mL) was added to a mixture of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (60 mg, 0.3 mmol) and 2-hydroxypyridine-N-oxide (HOPO) (30 mg, 0.27 mmol). The solution obtained was stirred at room temperature for 18 h then 1-acetylpiperazine (10 mg, 0.08 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (30 mg, 0.15 mmol) were added. After a further 3.5 h the reaction was purified using chromatography (silica gel, gradient 0 to 5% triethylamine/acetone) followed by preparative HPLC yielding Compound 66 as a white solid (32.2 mg).
Reaction SMILES: C([O:5]O)(C)(C)C.[Cl:7][C:8]1[CH:13]=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=1[NH:25][C:26](=[O:34])[C@:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:13]=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:5])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH:11]=[CH:10][C:9]=1[NH:25][C:26](=[O:34])[C@:27]([OH:33])([CH3:32])[C:28]([F:30])([F:31])[F:29]
Reactant: CC(C)(C)OO
Reactant: CSc1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)c1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
t-Butylhydroperoxide (0.36 ml of a 3M solution in toluene) was added to a solution of (R)-N-{2-chloro-4-[4-(methylsulphanyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 2) (0.247 g) and d-10-camphorsulphonic acid (0.012 g) in chloroform (5 ml) and the mixture was stirred at ambient temperature for 64 hours. The reaction mixture was transferred directly to a silica gel Mega Bond Elut column and eluted with 0-80% ethyl acetate/hexane to give the title compound (0.237 g) as a foam. NMR (CDCl3): 1.74 (s, 3H), 2.74 (s, 3H), 4.2 (brs, 1H), 7.79 (d, 2H), 7.89 (dd, 1H), 8.0 (m, 1H), 8.1 (d, 2H) 8.65 (d, 1H), 9.38 (brs, 1H); MS (ESP−): 468; EA: found: C, 43.3; H, 3.1; N, 2.98%; C17H15ClF3NO5S2 requires: C, 43.3; H, 3.1; N, 2.8%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2)#[N:2].[OH:34]O.[OH-].[Na+]>CS(C)=O.CCO>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2)(=[O:34])[NH2:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(C#N)ccc43)nc2c1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ccc2c(c1)CCCN2c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of methyl 3-(6-cyano-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.34 mmol) in DMSO (1.6 mL) and EtOH (6.4 mL) was added H2O2 (1.2 mL, 40%), NaOH (0.4 mL, 1M) with stirring overnight at room temperature. The resulting mixture was concentrated under vacuum, diluted with water (15 mL), adjusted pH to 7 with AcOH. The solids were collected by filtration to give 3-(6-carbamoyl-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a solid (131 mg, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)([CH2:11]2)[C:9]1=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li][CH3:24]>CCOCC.C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:13][CH:12]1[CH2:11][C:10]1([C:9](=[O:22])[CH3:24])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(Cl)c(Cl)c2)C1=O
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CC1CNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a flame-dried, 10 mL round-bottomed flask was added a solution of 1-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester in 2 mL of ether and 1.0 mL of THF under Ar (g). The solution was cooled in a dry ice/acetone bath with stirring. A solution of MeLi was added drop-wise and the resulting orange colored mixture was stirred at −78° C. for 3 hours. The solution was warmed to ambient temperature and quenched with 15 mL of 1N HCl. The organic layer was extracted with EtOAc (2×20 mL) and the combined layers washed with brine (20 mL). The organic layer was dried over sodium sulfate for 2 hours and filtered, concentrated under reduced pressure, and dried for 1 hour to afford 1.1 g of a brown oil. The oil was purified on a filter pad of silica eluting with 100/1 (v/v) CHCl3/MeOH. The desired fractions were collected, concentrated under reduced pressure, and dried to afford a yellow oil. Yield: 0.659 g 52%; 1H NMR (300 MHz, CDCl3) δ□7.46 (d, 1H, J=2.1 Hz, ArH), 7.39 (d, 1H, J=5.4 Hz, ArH), 7.20 (dd, 1H, J=5.4, 2.1 Hz, ArH), 4.73 (m, 1H, NH), 3.41 (m, 1H, CH2N), 3.15 (m, 1H, CH2N), 2.04 (s, 3H, CH3), 1.80 (m, CHCH2N), 1.45-1.58 (m, 9H, tert-Bu), 1.20 (dd, 2H, J=4.5 Hz, ArCCH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.Br[C:36]1[CH:37]=[CH:38][C:39]([OH:50])=[C:40]([C:42]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:43])[CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.ClCCl>[OH:50][C:39]1[CH:38]=[CH:37][C:36]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:12]3=[N:13][CH:14]=2)=[CH:41][C:40]=1[C:42]([N:44]1[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1)=[O:43]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C(c1cc(Br)ccc1O)N1CCOCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(O)c(C(=O)N4CCOCC4)c3)cc12
Yield: 30 %

Procedure:
A mixture of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.21 mmol), (5-bromo-2-hydroxy-phenyl)-morpholin-4-yl-methanone (66 mg (0.23 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (9 mg, 11 μmol) in acetonitrile (2 mL) and aqueous solution of sodium carbonate (2M, 2 mL) was irradiated in a Personal Chemistry Optimizer at 135° C. for 20 min. The crude reaction mixture was distributed between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueous phase was then extracted with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was then purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford {2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-morpholin-4-yl-methanone (35 mg, 30% yield) as a colorless solid. 1H-NMR (500 MHz, d6-DMSO) δ8.86 (d, 1H), 8.27 (d, 1H), 7.64 (dd, 1H), 7.62 (dd, 1H), 7.54 (d, 1H), 7.49 (ddd, 1H), 7.24 (d,br, 1H), 7.11 (ddd, 1H), 7.00 (d, 1H), 5.84 (s, 2H), 3.84 (s, 3H), 3.69 (t, 2H), 3.7-3.2 (m, 8H), 0.86 (t, 2H), −0.08 (s, 9H). MS: m/z 583 [MNa+], 561 [MH+], 443 [MH+-(Me3Si(CH2)2O)]
Reaction SMILES: [Cl-].[Li+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C1CCN2C(=NCCC2)CC1.[F:28][C:29]([F:35])([F:34])[CH2:30][CH2:31][CH:32]=O>CC#N>[F:28][C:29]([F:35])([F:34])[CH2:30][CH2:31]/[CH:32]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=CCCC(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C=C/CCC(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a suspension of lithium chloride (0.504 g, 11.9 mmol) in MeCN (20 mL) were added ethyl 2-(diethoxyphosphoryl)acetate (available from Aldrich) (1.91 mL, 9.52 mmol) and DBU (1.42 mL, 9.52 mmol) at room temperature. The mixture was cooled to 0° C., and 4,4,4-trifluorobutanal (available from Matrix Scientific) (1.00 g, 7.93 mmol) was added dropwise. The resulting mixture was warmed to room temperature and stirred overnight. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with additional EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford (E)-ethyl 6,6,6-trifluorohex-2-enoate 68.B (6:1 E/Z) as a colorless liquid (1.13 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15](Cl)=[O:16])=[CH:10][C:9]=2[CH3:18])=[O:7])=[CH:4][CH:3]=1.[O-2].[Mg+2].[NH2:23][C@H:24]([C:30]([OH:32])=[O:31])[CH2:25][CH2:26][C:27](=[O:29])[NH2:28].Cl>O1CCOCC1.O>[OH2:7].[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([NH:23][C@H:24]([C:30]([OH:32])=[O:31])[CH2:25][CH2:26][C:27](=[O:29])[NH2:28])=[O:16])=[CH:10][C:9]=2[CH3:18])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: Cc1cc(CC(=O)Cl)n(C)c1C(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(CC(=O)N[C@@H](CCC(N)=O)C(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 20.6 %

Procedure:
A solution of 30.5 g (0.1 mole) of [5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]-acetyl chloride in 150 ml of dioxane was added slowly at 0°-5° C. to a suspension of 5.88 g (0.15 mole) of magnesium oxide and 14.3 g (0.1 mole) of L-glutamine in 300 ml of water. The resulting yellow suspension was stirred at room temperature for 64 hours. The mixture was acidified with 1N hydrochloric acid and cooled. The precipitate was collected, washed with water and air dried. It was recrystallized three times from 2-propanol to give 10.8 g of light tan solid which was subjected to chromatography on silica gel. The column was eluted with chloroform:acetic acid:methanol (95:05:4.5). The major compound bearing fraction was concentrated to dryness and the residue recrystallized from acetone, water (2:1) to give 4.5 g (10% yield) of pale yellow crystalline N-{[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]-acetyl}-glutamine, hydrate (1:1), m.p. 186°-188° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:10]=1[CH2:11][O:12][C:13]1[C:14]2[N:15]([C:20]([C:24]([NH:26][CH2:27][C@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3C(OC(C)(C)C)=O)=[O:25])=[C:21]([CH3:23])[N:22]=2)[CH:16]=[C:17]([CH3:19])[CH:18]=1>Cl.C(OCC)C>[F:45][C:41]1[CH:42]=[CH:43][CH:44]=[C:9]([F:8])[C:10]=1[CH2:11][O:12][C:13]1[C:14]2[N:15]([C:20]([C:24]([NH:26][CH2:27][C@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]3)=[O:25])=[C:21]([CH3:23])[N:22]=2)[CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NC[C@H]3CCCCN3C(=O)OC(C)(C)C)n2c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NC[C@H]3CCCCN3)n2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
56 mg of tert-butyl (2R)-2-{[({8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]methyl}piperidin-1-carboxylate trifluoroacetate Example 183A (0.09 mmol) were initially charged in 2 M hydrochloric acid in diethyl ether, and the mixture was stirred at RT for 5 h. The resulting precipitate was filtered off and washed with diethyl ether, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate, filtered, concentrated and lyophilized. This gave 30 mg (78% of theory; purity 95%) of the title compound.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9]O.S(Cl)([Cl:13])=O>CN(C)C=O>[CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][Cl:13]
Reactant: O=c1cc(CO)occ1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=c1cc(CCl)occ1O
Temperature: 10 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
50 g(351.8 mmol) of kojic acid was dissolved in 250 ml of N,N-dimethylformamide. The resulting solution was cooled in a ice bath of 10° C. and 30 ml(411.3 mmole) of thionyl chloride was added dropwise thereto. The mixture was stirred at a room temperature for 2 hours and 2000 ml of ice water was added. The precipitates were filtered and dissolved into 1000 ml of ethyl acetate. The reaction product was dried over magnesium sulfate, decolored with active charcoal and filtered. The filtrate was concentrated and hexane was added to give crystals, which was then dried under vacuum to give 37.5 g(66.83%) of the desired chlorokojic acid as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([O:11][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:8][C@H:7]1[C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)N1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCOCC1
Reaction time: 1 h

Procedure:
To a solution of (1R,2R,4R)-4-hydroxy-2-(morpholine-4-carbonyl)-cyclopentanecarboxylic acid ethyl ester (1.0 mmol) in dichloromethane (5 ml) was added at 5° C. triethylamine (2.2 mmol) and methanesulfonyl chloride (2.2 mmol) and stirring was continued for 1 h. The mixture was partitioned between 1 N aqueous HCl and ethyl acetate, the organic layer was dried, evaporated and chromatographed on silica using ethyl acetate to give (1R,2R,4R)-4-methanesulfonyloxy-2-(morpholine-4-carbonyl)-cyclopentanecarboxylic acid ethyl ester as a colorless oil. MS: 350.4 (M+H)+.
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([OH:12])=[CH:7][C:6]=1[N:13]1[C:17](=[O:18])[C:16](=[C:19]([CH2:21][CH3:22])[CH3:20])[O:15][C:14]1=[O:23].C(=O)([O-])[O-].[K+].[K+].Br[CH:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CCOCC>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:37])=[CH:7][C:6]=1[N:13]1[C:17](=[O:18])[C:16](=[C:19]([CH2:21][CH3:22])[CH3:20])[O:15][C:14]1=[O:23]
Reactant: CCOC(=O)C(C)Br
Reactant: CCC(C)=C1OC(=O)N(c2cc(O)c(Cl)cc2Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1cc(N2C(=O)OC(=C(C)CC)C2=O)c(Cl)cc1Cl
Yield: 73 %

Procedure:
To an acetonitrile solution (30 ml) of a mixture of 3-(2',4'-dichloro-5'-hydroxyphenyl)-5-(sec-butylidene)-1,3-oxazolidine-2,4-dione (1.58 g, 5 mmol) was added potassium carbonate (0.69 g), and the mixture was heated at reflux for 2 hours. After the addition of ethyl 2-bromopropionate (0.93 g, 5.1 mmol), the reaction mixture was further refluxed for 1 hour. Ether was added to the reaction mixture and the solution was washed with 1N hydrochloric acid and extracted with ether. The ethereal extracts combined were dried and then evaporated as small a volume as possible. The resulting residue was purified by silica gel column chromatography to give 3-{2',4'-dichloro-5'-(1"-ethoxycarbonylethyloxy)phenyl}-5-(sec-butylidene)-1,3-oxazolidine-2,4-dione. (1.51 g, 73% yield)