Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=1[Cl:24].[NH+]1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:24][C:14]1[CH:15]=[C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][C:13]=1[NH:12][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1
Reactant: Fc1ccc2sc(Br)nc2c1
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1ccc(Nc2nc3cc(F)ccc3s2)c(Cl)c1
Yield: 37.5 %

Procedure:
In xylene (5 ml), 2-bromo-5-fluorobenzothiazole (516 mg, 2.22 mmol), methyl 4-amino-3-chlorophenylacetate (444 mg, 2.22 mmol), and pyridinium•p-toluenesulfonate (PPTS) (168 mg, 0.67 mmol) were heated under reflux for 10 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (7:1, v/v) eluate fractions, methyl (3-chloro-4-(5-fluoro-2-benzothiazolyl)aminophenyl)acetate (292 mg, 37%) was obtained as a pale yellow oil.
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([O:13][C:14]([N:16]1[CH2:19][C:18](=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18]([N:5]2[CH2:6][CH2:7][C:3]([F:8])([F:2])[CH2:4]2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: FC1(F)CCNC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCC(F)(F)C2)C1
Reaction time: 72 h
Yield: 62.9 %

Procedure:
A mixture of 3,3-difluoropyrrolidine hydrochloride (200 mg, 1.17 mmol), 3-oxoazetidine-1-carboxylic acid tert-butyl ester (284 mg, 1.99 mmol) and triethylamine (295 μL, 221 mg, 2.18 mmol) in DCE (10 mL) was stirred at room temperature for 1 h before the addition of sodium triacetoxyborohydride (745 mg, 3.52 mmol). The resulting mixture was stirred for 72 h then diluted with DCM and washed with H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-50%) affording 3-(3,3-Difluoropyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil (193 mg, 63%). 1H NMR (CDCl3, 300 MHz): δ 3.95 (m, 2H), 3.82 (dd, J=8.9, 4.9 Hz, 2H), 3.32 (m, 1H), 2.91 (m, 2H), 2.82-2.63 (m, 2H), 2.33-2.32 (m, 2H) and 1.43 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[C:9](=[N:19]/[OH:20])/[CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]1.CC(C)([O-])C.[K+]>C1COCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]([CH:10]3[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]3)=[N:19][O:20][C:2]=2[CH:7]=1
Reactant: CC(=O)N1CCC(/C(=N\O)c2ccc(Cl)cc2Cl)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2noc3cc(Cl)ccc23)CC1
Reaction time: 2 h
Yield: 74.3 %

Procedure:
1-(4-{(2,4-Dichloro-phenyl)-[(E)-hydroxyimino]-methyl}-piperidin-1-yl)-ethanone (2.15 g, 7 mmol) was solved in THF (34 mL) and potassium tert-butoxide was added (0.844 g, 7.5 mmol). The mixture was stirred for 2 hours until TLC indicated the end of the reaction. The solvent was removed and the mixture purified by flash-chromatography on silica gel with hexane:ethyl acetate (1:0 to 0:1). The combined producted fractions were evaporated under reduced pressure to yield 1.45 g of a colourless oil (75%). MS (m/e): 279.1 (M+H+).
Reaction SMILES: C([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])C1C=CC=CC=1>[Pd].C(O)C>[NH2:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N
Yield: 92 %

Procedure:
A solution of cis-ethyl 2-(benzylamino)cyclopentanecarboxylate (2.99 g, 12.1 mmol), prepared according to Bartoli, G. et al., J. Org. Chem., 59:5328-5335, was hydrogenated along with 500 mg 10% palladium on carbon in 20 mL ethanol at 45 psi for 22 h. The reaction was filtered through a 45μ filter and concentrated to give cis-ethyl 2-aminocyclopentanecarboxylate (1.75 g, 92%). 1H NMR (400 MHz, CDCl3) δ ppm 4.14 (2H, q, J=7.13 Hz), 3.53-3.62 (1H, m), 2.75 (1H, td, J=8.37, 6.67 Hz), 1.93-2.11 (1H, m), 1.77-1.92 (3H, m), 1.43-1.62 (2H, m), 1.35 (2H, s), 1.25 (3H, t, J=7.18 Hz). MS [M+H]+=158.24.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:12]([F:22])[C:11]2[C:7](=[C:8]([CH3:24])[N:9]([CH3:23])[N:10]=2)[CH:6]=1)=[O:4].C1C(=O)N([I:32])C(=O)C1.C(O)(C(F)(F)F)=O>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:32])=[CH:17][C:16]=2[F:21])=[C:12]([F:22])[C:11]2[C:7](=[C:8]([CH3:24])[N:9]([CH3:23])[N:10]=2)[CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc2c(C)n(C)nc2c(F)c1Nc1ccccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(C)n(C)nc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of 7-fluoro-6-(2-fluoro-phenylamino)-2,3-dimethyl-2H-indazole-5-carboxylic acid methyl ester (141 mg, 0.43 mmol) in DMF (5 ml) were added NIS (144 mg, 0.64 mmol) and TFA (0.20 mL), and the reaction was stirred at room temp for 4 h. The crude was diluted with EtOAc and washed with H2O. The organic fraction is dried over MgSO4 and concentrated under reduced pressure. Silica gel chromatography (EtOAc:Hexanes=75:25) yielded 137 mg (70%) of the title compound as a yellow solid.
Reaction SMILES: [F-:1].[F:2][C:3]([F:14])([C:11](Cl)=[O:12])[O:4][C:5]([F:10])([F:9])[C:6](Cl)=[O:7].[F-:15].[Na+]>C(#N)C>[F:2][C:3]([F:14])([C:11]([F:15])=[O:12])[O:4][C:5]([F:10])([F:9])[C:6]([F:1])=[O:7]
Reactant: O=C(Cl)C(F)(F)OC(F)(F)C(=O)Cl
Reactant: [F-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(F)C(F)(F)OC(F)(F)C(=O)F
Reaction time: 8 h

Procedure:
Conversion of the diacid chloride to the corresponding fluoride, bp 32°-33° C., was accomplished by a scale-up of the procedure of R. E. Banks, E. D. Burling, B. A. Dodd, and K. Mullen, J. Chem. Soc. (c), 1706 (1969). A mixture of 215 g (0.885 mol) of tetrafluorodiglycolyl dichloride, 140.5 g (3.35 mol) of NaF, and 1200 ml of anhydrous acetonitrile was stirred overnight, then distilled to give a fraction collected at 35°-79° C. The distillate was treated with 20 g of NaF and distilled to give 105 g of tetrafluorodiglycolyl difluoride, bp 32°-33° C. Additon of another 100 g (2.38 mol) of NaF to the reaction mixture and slow distillation afforded another fraction, bp 35°-81° C. Treatment with 10 g of NaF and fractionation gave another 37.0 g of difluoride product, bp 32°-33° C., for a total of 142 g (76%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH:27]([F:29])[F:28])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.[CH3:32][C:33]([CH3:35])=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:14][C:11]1[C:12]([F:13])=[C:7]([CH:5]2[CH2:6][N:3]([CH:33]([CH3:35])[CH3:32])[CH2:4]2)[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH:27]([F:29])[F:28])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.9 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (45 mg, 0.090 mmol), acetone (37 mg, 0.63 mmol) and triethylamine (63 μL, 0.45 mmol) in methylene chloride (0.9 mL) was added sodium triacetoxyborohydride resin (0.12 g, 0.27 mmol). The mixture was stirred at room temperature for 2 h, then filtered, concentrated and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.5 mg, 6.8%). The product was isolated as a racemic mixture. LCMS calculated for C21H25ClF3N6O (M+H)+: m/z=469.2; Found: 469.2.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[O:13][C:14]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[N:15][N:16]=1>N1C=CC=CC=1>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:14]1[O:13][C:12]([NH:11][C:6]([C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)=[O:7])=[N:16][N:15]=1
Reactant: Nc1nnc(-c2ccco2)o1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: c1ccncc1
Product: O=C(Nc1nnc(-c2ccco2)o1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.1 %

Procedure:
4-Iodobenzoyl chloride (2.65 g, 9.95 mmol) was gradually added to a solution of commercially available 2-amino-5-(2-furyl)-1,3,4-oxadiazole (1.00 g, 6.62 mmol) in pyridine (20 mL), followed by stirring at room temperature for 2.5 hr and then at 50° C. overnight. The reaction solution was concentrated. Water and methylene chloride were added to the residue, and precipitated crystals were collected by filtration. The crystals were washed with water and methylene chloride and then dried to obtain the title compound (1.39 g, 3.65 mmol) (yield: 55%).
Reaction SMILES: ClC1C=C2C(C(=O)C(=O)N2)=CC=1.ClC1C=C2C(C(=O)C(=O)N2)=CC=1[N+]([O-])=O.ClC1C=C2C(C=CN2)=CC=1[N+]([O-])=O.[Cl:41][C:42]1[CH:50]=[C:49]2[C:45]([C:46]([CH2:51][C:52]#[N:53])=[CH:47][NH:48]2)=[CH:44][C:43]=1[N+:54]([O-])=O.[H][H]>[Pd].CCO>[NH2:54][C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][C:42]=1[Cl:41])[NH:48][CH:47]=[C:46]2[CH2:51][C:52]#[N:53]
Reactant: [H][H]
Reactant: N#CCc1c[nH]c2cc(Cl)c([N+](=O)[O-])cc12
Agent: [Pd]
Agent: O=C1Nc2cc(Cl)c([N+](=O)[O-])cc2C1=O
Agent: O=C1Nc2cc(Cl)ccc2C1=O
Solvent: CCO
Product: N#CCc1c[nH]c2cc(Cl)c(N)cc12

Procedure:
This intermediate was prepared by the sequence 6-chloroisatin, 6-chloro-5-nitroisatin, 6-chloro-5-nitroindole, 6-chloro-5-nitrogramine and 6-chloro-5-nitroindole-3-acetonitrile which was hydrogenated with 10% Pd/C until 3 equiv. of hydrogen were taken up. The catalyst was removed by filtration and the residue concentrated in vacuo to give a dark brown solid. Trituration with cold EtOH gave desired pure product.
Reaction SMILES: O[C:2]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1>C(O)=O>[C:9]1([C:2]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)=[CH:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CCc2cc(C(O)(Cn3ccnc3)c3ccccc3)ccc2N1
Solvent: O=CO
Product: O=C1CCc2cc(C(=Cn3ccnc3)c3ccccc3)ccc2N1

Procedure:
A solution of 600 mg of 6-[1-hydroxy-1-phenyl-2-(imidazol-1-yl)ethyl]-3,4-dihydrocarbostyril in 20 ml of anhydrous formic acid was refluxed for 24 hours. The solvent was removed under reduced pressure and the residue partitioned between 5% methanol in methylene chloride and aqueous potassium carbonate. The organic solution was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 5% methanol in methylene chloride, affording 6-[1-phenyl-2-(imidazol-1-yl)ethenyl]-3,4-dihydrocarbostyril as a mixture of (E) and (Z) isomers. 1H NMR of major isomer (CDCl3) δ2.64 (d, 1H, J=8.0 Hz), 2.65 (d, 1H, J=8.0 Hz), 2.94 (t, 2H, J=8.0 Hz), 6.60 (t, 1H, J=1.33 Hz), 6.77 (d, 1H, J=8.1 Hz), 6.90 (t, 1H, J=1.1 Hz), 6.94-7.40 (series of unresolved multiplets, 9H), 8.50 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[O:32]1[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([S:42](Cl)(=[O:44])=[O:43])[C:36]=2[O:35][CH2:34][CH2:33]1>>[O:32]1[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([S:42]([N:5]3[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:2]([CH3:1])[C:3]([CH:13]=[O:14])=[CH:4]3)(=[O:44])=[O:43])[C:36]=2[O:35][CH2:34][CH2:33]1
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1
Reactant: O=S(=O)(Cl)c1cccc2c1OCCO2
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1c(C=O)cn(S(=O)(=O)c2cccc3c2OCCO3)c1-c1ccccc1

Procedure:
Using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 116 mg), 15-crown-5 (881 mg) and 2,3-dihydro-1,4-benzodioxine-5-sulfonyl chloride (516 mg), a procedure as in Reference Example 219 was performed to give the title compound as a pale-yellow amorphous (yield 295 mg, 77%).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C:6](=O)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])C.[C:16]1(C=C[CH:21]=[C:19](O)[CH:18]=1)[OH:17].Cl>C(O)C>[OH:17][C:16]1[CH:13]=[C:12]2[C:21]([C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:15])=[CH:8][C:9](=[O:10])[O:11]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)CCC(=O)CC(=O)OCC
Reactant: Oc1cccc(O)c1
Agent: Cl
Solvent: CCO
Product: O=C(O)CCc1cc(=O)oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of 3-oxohexane-1,6-dioic acid diethyl ester (78.88 g), resorcinol (40.19 g) and ethanol (1 L) was saturated with hydrogen chloride gas during two hours at 0° C., tightly stoppered, let stand at room temperature over the weekend, shown by thin layer chromatography to contain unreacted 3-oxohexane-1,6-dioic acid diethyl ester, saturated again with hydrogen chloride gas during 45 minutes at 0° C., and let stand overnight at room temperature. Although thin layer chromatography still showed that the reaction was incomplete, the solution was partially (800 mL) stripped of volatiles and poured into ice-water. The resulting solid was collected by filtration and ethanol (300 mL) and aqueous sodium hydroxide solution (2.5N, 350 mL) were added. The mixture was stirred at room temperature and, when the reaction was complete, poured into hydrochloric acid (2N, 500 mL). A suspension of the resulting solid in methanol (300 mL) was stirred for 15 minutes at room temperature, cooled on ice and filtered. The resulting solid was washed with ether and dried affording 3-(7-hydroxy-4-coumarinyl)propionic acid (62.4 g, 73% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][C:43]1[S:44][CH:45]=[C:46]([CH2:48]O)[N:47]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.ClCCl>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:48][C:46]5[N:47]=[C:43]([CH3:42])[S:44][CH:45]=5)[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Reactant: Cc1nc(CO)cs1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(OCc2csc(C)n2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 76.3 %

Procedure:
A mixture of 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 0.100 g, 0.315 mmol) and triphenylphosphine (0.123 g, 0.47 mmol) was maintained under vacuum for 10 minutes. The mixture was flushed with nitrogen and then charged with dry THF (8 mL) and (2-methylthiazol-4-yl)methanol (Example 1A, 0.049 g, 0.38 mmol). The mixture was warmed to 50° C. and sonicated for 5 minutes. The cooled mixture was treated with a solution of DIAD (0.096 g, 0.47 mmol) in dry THF (2 mL) added in three portions dropwise over 20 minutes. The mixture was homogeneous after 40 min. and was stirred at 22° C. for 6 h. The reaction mixture was diluted with dichloromethane (250 mL), washed with sat. sodium bicarbonate, brine and dried over anhydrous MgSO4. Evaporation gave a semi-solid residue which was purified by chromatography on silica gel (2.5×10 cm, dichloromethane/EtOAc 8:2) to provide the title material (0.103 g, 76%) as white cubes. LC (Method A): 2.224 min. HRMS (ESI) calcd for C19H17N4O4S2 [M+H]+ m/z 429.0686, found 429.0605. 1H NMR (CDCl3, 600 MHz) δ 7.82 (s, 1H), 7.17 (s, 1H), 7.06 (s, 1H), 6.67 (m, 1H), 6.39 (d, J=1.89 Hz, 1H), 5.25 (d, J=0.9 Hz, 2H), 4.18 (s, 3H), 3.82 (s, 3H), 2.72 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@:11]2([O:18]C)[C:13](=[O:17])[NH:14][C:15](=[O:16])[C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][C@:11]2([OH:18])[C:13](=[O:17])[NH:14][C:15](=[O:16])[C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@]12CN(Cc3ccccc3)C[C@H]1C(=O)NC2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1NC(=O)[C@@]2(O)CN(Cc3ccccc3)C[C@@H]12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled −78° C. solution of (cis)-5-benzyl-3a-methoxytetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (403 mg, 1.55 mmol) in DCM (5.15 mL was added BBr3 (0.293 mL, 3.10 mmol). After 1 hr, the reaction mixture was warmed to 0° C. and stirred for an additional 1 hr and eventually warmed to rt and stirred for 24 hrs. The reaction mixture was cooled to 0° C., quenched with MeOH until the evolution of gas subsided. The mixture was concentrated and the residue was redissolved in MeOH (4 mL). Pd/C (40 mg) and was added and stirred under nitrogen to remove the borane (org letters, 2001, p 465-467) for 72 hrs. The mixture was filtered and concentrated to afford the crude title compound that was carried forward to the next step without further purification. m/z (APCI+) for C13H14N2O3 247.10 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[O-].[Na+].Cl[C:13](=[N:18]O)[C:14]([O:16][CH3:17])=[O:15]>CO>[CH3:5][C:3]1[O:4][N:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:2]=1[C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: COC(=O)C(Cl)=NO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1noc(C)c1C(=O)OC
Reaction time: 3 h
Yield: 37.9 %

Procedure:
23.2 g (0.2 mol) of methyl acetoacetate in 50 ml of absolute methanol are added to a solution of 10.8 g (0.2 mol) of sodium methylate (cryst.) in 150 ml of dry methanol at 0°-10° C., and the mixture is stirred at this temperature for 3 h. Subsequently, at 0°-10° C., 27.5 g (0.2 mol) of methyl α-chloro-α-hydroximinoacetate in 100 ml of absolute methanol are slowly added dropwise, and the mixture is stirred at room temperature for 12 h. The solution is worked up by evaporation to a small volume and addition of 800 ml of water, when the product separates out as oil. The organic phase is separated off, the aqueous phase is extracted with dichloromethane, the combined organic phases are dried, and the solvent is stripped off in a rotary evaporator. The residue is purified by column chromatography on silica gel (solvent cyclohexane/ethyl acetate 3:1). 15.1 g (38% of theory) of dimethyl 5-methylisoxazole- 3,4-dicarboxylate are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]([N+:18]([O-])=O)=[CH:16][C:6]2[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][O:14][CH3:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1.O.NN>[Pd].CO>[CH3:1][O:2][C:3]1[C:17]([NH2:18])=[CH:16][C:6]2[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][O:14][CH3:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COCCN1CCc2cc(OC)c([N+](=O)[O-])cc2CC1
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: O
Product: COCCN1CCc2cc(N)c(OC)cc2CC1
Temperature: 70 °C
Yield: 93.3 %

Procedure:
Into a 1-neck round-bottom flask was added 7-methoxy-3-(2-methoxy-ethyl)-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.4 g, 8.56 mmol), hydrazine monohydrate (20 mL, 0.4 mol), and palladium on carbon (10% wt, 50% wet; 400 mg), in methanol (80 mL). The reaction mixture was heated at 70° C. for 3 hours. The reaction mixture was filtered through Celite and was concentrated. The residue was partitioned between diluted NaHCO3 and ethyl acetate. The aqueous phase was extracted with another portion of ethyl acetate, dried (MgSO4), and concentrated to afford 8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (2.00 g, 93%). 1H-NMR (CDCl3) δ 6.55 (s, 1H), 6.49 (s, 1H), 3.81 (s, 3H), 3.63 (br s, 2H), 3.53 (t, J=5.8 Hz, 2H), 3.36 (s, 3H), 2.60-2.90 (m, 10H); LC/MS (ESI+): 251.10 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10](Cl)(=[O:12])=[O:11])=[C:5]([CH3:14])[C:4]=1[CH3:15].[CH3:16][NH:17][CH2:18][CH2:19][OH:20].CCN(CC)CC>C1COCC1>[OH:20][CH2:19][CH2:18][N:17]([CH3:16])[S:10]([C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:15])[C:5]=1[CH3:14])(=[O:12])=[O:11]
Reactant: CNCCO
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)CCO)c(C)c1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A soln. of 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride (2.29 g, 9.19 mmol) in THF (30 ml) was added dropwise to a soln. of 2-methylaminoethanol (0.89 g, 0.95 ml, 11.8 mmol) and Et3N (5 ml) in THF (15 ml) at 0° C. The mixture was subsequently stirred at RT for 5 h and then concentrated i. vac., the residue was taken up in NaHCO3 soln. and the mixture was extracted with EtOAc (3×30 ml). The combined organic phases were dried with Na2SO4 and concentrated i. vac.
Reaction SMILES: C([O:8][C:9]1[C:10]([N:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:11]([F:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)C1C=CC=CC=1.[CH3:29][C:30]([CH3:37])([CH2:34][CH:35]=[CH2:36])[C:31]([OH:33])=[O:32].B1C2CCCC1CCC2>[OH-].[OH-].[Pd+2].[Pd]>[F:20][C:11]1[C:10]([N:21]2[CH2:22][C:23](=[O:28])[NH:24][S:25]2(=[O:27])=[O:26])=[C:9]([OH:8])[CH:18]=[C:17]2[C:12]=1[CH:13]=[C:14]([CH2:36][CH2:35][CH2:34][C:30]([CH3:37])([CH3:29])[C:31]([OH:33])=[O:32])[CH:15]=[CH:16]2
Reactant: C=CCC(C)(C)C(=O)O
Reactant: O=C1CN(c2c(OCc3ccccc3)cc3ccc(Br)cc3c2F)S(=O)(=O)N1
Agent: [Pd+2]
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Product: CC(C)(CCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)c(F)c2c1)C(=O)O

Procedure:
This compound is prepared from 5-(3-benzyloxy-7-bromo-1-fluoronaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and 2,2-dimethyl-pent-4-enoic acid-9-BBN similar to Example 8, Steps A and B, except in Step B, Pd(OH)2 is used to replace 10% Pd/C: Retention time=0.98 min (Method A); MS (M−H)−=423.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17](O)=[O:18].[NH2:20][C:21]1[S:25][CH:24]=[C:23]([C:26]#[N:27])[C:22]=1[C:28]1[S:32][CH:31]=[N:30][CH:29]=1>>[C:26]([C:23]1[C:22]([C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[C:21]([NH:20][C:17](=[O:18])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:25][CH:24]=1)#[N:27]
Reactant: N#Cc1csc(N)c1-c1cncs1
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Product: N#Cc1csc(NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)c1-c1cncs1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.047 g, 0.17 mmol) and 5-amino-4-(thiazol-5-yl)thiophene-3-carbonitrile (0.055, 0.26 mmol) according to protocol A. The crude product was purified by prep HPLC. Retention time (min)=5.989, method [7], MS (ESI) 461.1 (M+H). 1H NMR (CDCl3) δ 9.95 (s, 1H), 7.91-7.85 (m, 4H) 7.78 (d, J=8.7 Hz, 1H), 7.63 (s, 1H), 6.84 (d, J=8.7 Hz, 1H), 5.06 (s, 2H).