Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10]([C:20](O)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=C=O)=[CH:27][CH:26]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10]([C:20]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:34])[F:35])=[CH:26][CH:27]=3)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)C1=NN(c2cccc(Cl)c2)C(c2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(F)(F)F)cc1)C1=NN(c2cccc(Cl)c2)C(c2ccccc2)CC1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
To 0.70 g (0.0022 mol) of the product obtained in Step B, dissolved in 10 mL toluene, was added 0.625 g (0.0030 mol) α,α,α-trifluoro-p-tolylisocyanate and 0.30 g (0.0029 mol) triethylamine. The reaction mixture was heated at reflux for 18 h, cooled to room temperature and concentrated under reduced pressure. The crude product was triturated with ether to afford 0.50 g of a white solid, mp 183°-184° C.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([NH:30][CH2:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[N:26]=[C:25]([CH3:37])[N:24]=2)=[O:20])[CH2:8][N:9]([O:12]C2CCCCO2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O>O>[CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([NH:30][CH2:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[N:26]=[C:25]([CH3:37])[N:24]=2)=[O:20])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NCc2nccs2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(NCc2nccs2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)n1
Yield: 51.1 %

Procedure:
[(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (67 mg, 0.13 mmol) in 4:1 AcOH:water (5 mL) was stirred at room temperature overnight. The solvents were removed in vacuo, and the resulting crude product was purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide (30 mg, 51%). LCMS: (M+H)+: 452.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][C:11]=2[CH:21]=1)=[O:5])[CH3:2].[CH3:22][O:23][CH2:24][C@H]1COC(=O)O1>>[C:15]1([C:13]2[O:14][C:10]3[CH:9]=[CH:8][C:7]([N:6]4[CH2:2][C@H:1]([CH2:22][O:23][CH3:24])[O:3][C:4]4=[O:5])=[CH:21][C:11]=3[CH:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)Nc1ccc2oc(-c3ccccc3)cc2c1
Reactant: COC[C@H]1COC(=O)O1
Product: COC[C@H]1CN(c2ccc3oc(-c4ccccc4)cc3c2)C(=O)O1

Procedure:
3.1 g (11 mmol) of 5-ethoxycarbonylamino-2-phenylbenzofuran are treated with 4(S)-methoxymethyl-1,3-dioxolan-2-one under the conditions described in step 4 of Example 1. 2.5 g of product are obtained. Melting point: 178.5-179.3° C.
Reaction SMILES: [NH2:1][C@@H]1C2CCN(CC2)[C@H]1CC1C=NC=CC=1.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=1)[C:21](O)=[O:22].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=1)[C:21]([NH2:1])=[O:22]
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: N[C@@H]1C2CCN(CC2)[C@H]1Cc1cccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a suspension of (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (20 mg, 0.092 mmol, prepared as described in PCT WO 09/018505, herein incorporated by reference with regard to such synthesis), o-(benzotriazol-1-yl)-N,N,N,1-tetramethyluronium hexafluorophosphate (HBTU, 41.7 mg, 0.110 mmol) and 3,5-difluorobenzoic acid (17.4 mg, 0.110 mmol) in N,N-dimethylformamide (DMF, 2 ml) was added triethylamine (28 mg, 0.28 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate (200 ml) and washed with 20% aqueous potassium carbonate. The residue was purified by silica gel chromatography with the eluent methanol:triethylamine=300:1. The solvent was removed to give (2S,3R)—N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide (30 mg, 76%), purity by HPLC: 100% (214 nm), 98.2% (254 nm); 1H NMR (400 MHz, CDCl3) d 8.48 (d, j=2.0 Hz, 1H), 8.36 (dd, j=1.7 Hz, j=4.9 Hz, 1H), 7.56-7.60 (m, 1H), 7.14-7.20 (m, 1H), 7.05-7.14 (m, 2H), 6.87-6.96 (m, 1H), 6.23 (d, j=7.8 Hz, 1H), 3.88-3.96 (m, 1H), 3.02-3.13 (m, 1H), 2.82-3.00 (m, 4H), 2.65-2.82 (m, 2H), 1.97-2.05 (m, 1H), 1.58-1.84 (m, 3H), 1.43-1.55 (m, 1H); ESI-MS 358.1 (MH)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH:42]=O.CCN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([CH2:42][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: O=Cc1ccccn1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(Cc4ccccn4)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 77.5 %

Procedure:
A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (88 mg, 0.18 mmol) (as prepared in Example 14, step (b)), pyridine-2-carbaldehyde (17 μL, 0.21 mmol), NEt3 (30 μL, 0.21 mmol), sodium triacetoxyborohydride (56 mg, 0.25 mmol) and 0.8 mL of 1,2-dichloroethane and stirred for 10 h at 25° C. The solvent was evaporated, and the title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA/H2O over 20 min to give 81 mg (78%) of a white solid. 1H-NMR (400 MHz, DMSO-d6): δ 14.25 (br s, 1H), 9.90 (br s, 1H), 9.79 (s, 1H), 8.72 (s, 1H), 8.36 (s, 1H), 7.98 (m, 1H), 7.88 (dd, 1H), 7.58 (d, 1H), 7.52 (m, 1H), 7.20 (m, 1H), 7.12 (d, 1H), 5.76 (m, 1H), 4.56 (s, 2H), 3.40 (m, 2H), 3.18 (m, 2H), 2.88 (m, 1H), 2.20 (m, 4H), 2.00 (m, 4H), 1.72 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C28H30N6O, 467.2 (M+H), found 467.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)(=O)C.CCCCCC>[C:10]1([CH2:9][CH2:8][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: C=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1ccc(CCNc2ccccc2)cc1
Yield: 78 %

Procedure:
According to GWM, 0.011 mol (=1.00 ml) of aniline and 0.011 mol (=1.25 ml) of styrene are reacted with one another. The product is isolated by column chromatography using ethyl acetate/n-hexane (1:3) as eluent, the product N-phenylethylaniline being obtained as a yellow liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.Cl[Si:10]([CH2:17][CH2:18][CH3:19])([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13]>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Si:10]([CH2:17][CH2:18][CH3:19])([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:3]=1
Reactant: CCC[Si](Cl)(CCC)CCC
Reactant: Brc1cccc(Br)c1
Product: CCC[Si](CCC)(CCC)c1cccc(Br)c1

Procedure:
1-Bromo-3-tri-n-propylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing 1,3-dibromobenzene and chloro-tri-n-propylsilane as the ClSiR1R2R3 compound.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][Si:26]([CH3:38])([CH3:37])NS(C1C=CC=CC=1)(=O)=O.[Br:39]N1C(=O)CCC1=O>ClCCl>[Br:39][CH2:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([O:10][Si:26]([CH3:38])([CH3:37])[CH3:25])=[O:9]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Reactant: C[Si](C)(C)NS(=O)(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Reaction time: 1 h
Yield: 44 %

Procedure:
352 mg (1.01 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide were added to a solution of 0.45 mg (2.0 mmoles) of N-trimethylsilylbenzenesulfonamide in 70 ml of dichloromethane and after refluxing for half an hour a still slightly turbid solution was obtained. An additional 0.42 g of N-trimethylsilylbenzenesulfonamide (1.8 mmoles) was added and refluxing was continued for half an hour. The clear, light yellow solution obtained was cooled in an ice-bath and bromination was carried out in one hour using 0.26 mg (1.46 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 44% yield of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[CH3:11]SC(=N)N.C(N([CH2:21][CH3:22])CC)C.[O:23]1[CH2:28][CH2:27]OCC1>>[CH3:6][S:7][C:8]1[NH:9][C:28](=[O:23])[C:27]2[CH2:22][CH2:21][C:11]=2[N:10]=1
Reactant: CCN(CC)CC
Reactant: CSC(=N)N
Reactant: C1COCCO1
Agent: O=S(=O)(O)O
Product: CSc1nc2c(c(=O)[nH]1)CC2
Temperature: 50 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
In 50 mL of dry reaction flask methyl 2-chloro-2-cyclopropylidineacetate (365 mg, 2.50 mmol), S-methylisothiourea hemisulphate (see formula 2g) (1.392 g, 5.00 mmol) and triethylamine (1.52 g, 15.0 mmol) in 25 mL of anhydrous dioxane are stirred at 50° C. for 48 h. After filtration, the solid residue is suspended in DCM (25 mL) and washed with water. The aq. layer is extracted with DCM (2×25 mL). After removing the solvent in vacuum, the crude product is subjected to column chromatography (Rf=0.3, DCM/MeOH=25:1, 1.5×30 cm, 30 g SiO2) to yield 310 mg (74%) of the compound of formula 3g as a white solid, m.p. 215° C. —IR (KBr): nu(tilde)=2996 cm−1, 2928, 1654, 1541, 1456, 1396, 1297, 1189, 922, 751. —1H NMR (250 MHz, CDCl3): δ=2.58 (s, 3H, SMe), 2.95 (t, J=3.1 Hz, 2H, CH2), 3.15 (t, J=3.1 Hz, 2H, CH2), 11.5 (br. s, 1H, NH). —13C NMR (62.9 MHz, [D6]DMSO): 13.4 (+), 24.9 (−), 33.2 (+), 120.4 (C-6), 152.3 (C-1/C-3), 156.6 (C-3/C-1), 164.98 (C-5). —MS (70 eV), m/z (%): 169 (12) [M++1], 168 (100) [M+], 121 (14) [M+−SMe], 93 (22), 74 (16). —C7H8N2OS (168.2): calcd. C, 49.98; H, 4.79; N, 16.65. found C, 49.66; H, 5.14; N, 16.50.
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=1)[CH:7]=[CH:6][CH:5]=2.[CH:25]1([Mg]Br)[CH2:27][CH2:26]1.O1CCCC1.Cl>C1(C)C=CC=CC=1>[CH:25]1([C:2]2[CH2:3][C:4]3[C:9]([CH:10]=2)=[C:8]([C:11]2[CH:12]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:16]=2)[CH:7]=[CH:6][CH:5]=3)[CH2:27][CH2:26]1
Reactant: Br[Mg]C1CC1
Reactant: CC(C)(C)c1cc(-c2cccc3c2C=C(Br)C3)cc(C(C)(C)C)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-c2cccc3c2C=C(C2CC2)C3)cc(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
A solution of compound 6 (16.1 g, 42.0 mmol, 1 equiv) and anhydrous toluene (200 mL) was treated with [1,1′-bis(diphenylphos-phino)ferrocene]dichlopalladium(II) DCM adduct (3.43 g, 4.2 mmol, 0.1 equiv). After stirring for 10 minutes, 0.5 M cyclopropylmagnesium bromide in tetrahydrofuran (420 mL, 210 mmol, 5 equiv) was added dropwise. The reaction was heated at 60° C. overnight. The reaction was cooled with an ice bath, acidified with 1N HCl to pH 3 and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with saturated brine (800 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on an AnaLogix (65-200 g) column with dry-loading, eluting with heptanes to give compound 7 (7.0 g, 48% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.[NH2:18][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:20]O.O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:22]([CH:19]1[CH2:20][N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:18]1)[CH2:23][CH3:24]
Reactant: CCCC(N)CO
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCC1CN2N=C(c3cccc(C(F)(F)F)c3)C=CC2=N1
Temperature: 130 °C

Procedure:
A mixture of 5.0 g of 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine and 10 g of 2-amino-1-pentanol is heated at 130° C. for 24 hours, cooled, poured into water and extracted with dichloromethane. As for Example 3, the obtained product is reacted with thionyl chloride and the ring is closed with potassium carbonate in ethanol to give 2,3-dihydro-2-propyl-6-[3-(trifluoromethyl)phenyl]imidazo[1,2-b]pyridazine which is dehydrogenated with lead tetraacetate to obtain the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].Cl[CH2:19][CH2:20][CH2:21][CH2:22][OH:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]
Reactant: OCCCCCl
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Product: OCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl

Procedure:
In a second series of steps, 2,6-dichloro-4-phenylmethoxyphenol (known compound) was reacted under basic conditions with, for example 4-chlorobutan-1-ol, as a means of attaching bridging group B, yielding the corresponding intermediate 4-[2,6-dichloro-4-(phenylmethoxy)phenoxy]butan-1-ol (H). Intermediate (H) was then de-protected by cleavage of the phenylmethyl moiety using hydrogenation under catalytic conditions affording the corresponding phenol intermediate (J), which was in turn reacted with, for example 1,1,1,3-tetrachloropropane under basic conditions, affording the corresponding butanol intermediate (K). Intermediate (K) was then brominated with, for example carbon tetrabromide and triphenylphosphine, providing the corresponding bromobutane intermediate (L). Intermediate (L) was in turn reacted with intermediate (G) under basic conditions, affording a compound of formula I where, for example R8 is trifluoromethyl (Compound 20). Example 3 set forth below, provides a detailed method to how Compound 20 shown in Scheme 3 was prepared.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:42])[O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl.CCOCC>[CH:36]1([O:35][C:34](=[O:42])[NH:1][CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:4]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(Cl)OC1CCCCC1
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(CNC(=O)OC2CCCCC2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product of Example 42 (90 mg, 0.26 mmol), iPr2NEt (0.078 mL, 0.45 mmol), and cyclohexyl carbonochloridate (51.2 mg, 0.315 mmol) in DCM (4 mL) was stirred at room temperature for 8 hours, diluted with Et2O, washed with sat NaHCO3 and brine, dried (MgSO4), filtered, concentrated, and chromatographed (17-25% EtOAc/DCM) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.60 (s, 1H), 8.32 (dd, J=7.8, 1.4 Hz, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.97-8.03 (m, 1H), 7.91 (td, J=7.5, 1.2 Hz, 1H), 7.60-7.65 (m, 1H), 7.41 (s, 4H), 4.47-4.51 (m, 3H), 3.67 (s, 2H), 1.58-1.84 (m, 4H), 1.41-1.54 (m, 1H), 1.10-1.35 (m, 4H); MS (ESI−) M/Z 467 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:20])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCCCC2)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCCCC2)c1C
Temperature: 80 °C
Yield: 55.2 %

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclohexylamino)-2-methylbenzoate (1.4 g, 0.0049 mole) in acetonitrile (10 mL), cesium carbonate (3.2 g, 0.0099 mole) and methyl iodide (3.5 g, 0.0024 mole) were added; resulting reaction mass was heated at 80° C. for 13 h. On completion, reaction mass was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated and then purified by column chromatography to afford desired compound (800 mg, 55%).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[F:16])([CH3:6])([CH3:5])[CH3:4].O>CO>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[F:16])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(N)cc1F
Reaction time: 0.03 h
Yield: 74 %

Procedure:
NaBH4 (144 mg, 152 μL, 3.8 mmol) was added to a solution of 1-tert-butyl-2-fluoro-4-nitro-benzene (750 mg, 3.8 mmol) and NiCl2.6H2O (2.6 g, 11 mmol) in methanol (15 mL) at −15° C. After addition, the mixture was stirred for 2 minutes and water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated in vacuo to afford 4-tert-butyl-3-fluoro-aniline (470 mg, 74%) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 7.08-7.02 (m, 1H), 6.42-6.34 (m, 2H), 1.32 (s, 9H). MS (ESI) m/z: 168.2 [M+H]
Reaction SMILES: ClC([O:4][CH2:5]C(CC)CCCC)=O.[C:13]([NH:16][C:17]1[S:18][C:19]([C:23]2[N:24]=[C:25]([NH:28][C:29]3[CH:30]=[C:31]([C:35](=[N:37][OH:38])O)[CH:32]=[CH:33][CH:34]=3)[S:26][CH:27]=2)=[C:20]([CH3:22])[N:21]=1)(=[O:15])[CH3:14].[N:39]1C=CC=CC=1>CN(C=O)C.O>[OH:4][C:5]1[O:38][N:37]=[C:35]([C:31]2[CH:30]=[C:29]([NH:28][C:25]3[S:26][CH:27]=[C:23]([C:19]4[S:18][C:17]([NH:16][C:13](=[O:15])[CH3:14])=[N:21][C:20]=4[CH3:22])[N:24]=3)[CH:34]=[CH:33][CH:32]=2)[N:39]=1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(Nc3cccc(C(O)=NO)c3)n2)s1
Reactant: c1ccncc1
Reactant: CCCCC(CC)COC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(-c2csc(Nc3cccc(-c4noc(O)n4)c3)n2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Ethylhexyl chloroformate (101.22 μl; 0.51 mmol; 1.00 eq.) is added dropwise to an ice cooling mixture of 3-{[2′-(acetylamino)-4′-methyl-4,5′-bi-1,3-thiazol-2-yl]amino}-N-hydroxybenzenecarboximidic acid (60) obtained as described above in Example 60 (200.00 mg; 0.51 mmol; 1.00 eq.) and anhydrous pyridine (41.56 μl; 0.51 mmol; 1.00 eq.) in DMF (2.00 ml). The resulting mixture is stirred at 0° C. for 30 min. It is diluted with water and extracted with EtOAc (3 times). The extracts are washed with water and dried over Na2SO4. Solvents are evaporated and the resulting crude intermediate is suspended 1 to in xylene (2 mL) and heated at 150° C. for 2 hours. The solvents are evaporated and the resulting crude product is purified by flash chromatography, affording N-(2-{[3-(5-hydroxy-1,2,4-oxadiazol-3-yl)phenyl]amino}-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl)acetamide (61) as parent (134.90 mg; 64.70%). A sample (88.00 mg; 0.21 mmol; 1.00 eq.) is suspended in water (2.50 ml) and THF (2.50 ml) and potassium hydroxide solution (416.15 μl; 0.50 M; 0.21 mmol; 0.98 eq.) is added. The resulting solution is filtered through cotton and freeze-dried, affording (61) as brown powder (82.8 mg; 91.58%). 1H NMR (DMSO-d6, 300 MHz) δ 2.12 (s, 3H), 2.52 (s, 3H, COCH3), 6.88 (s, 1H), 7.34 (m, 2H), 7.84 (m, 2H), 10.34 (s, 1H). M− (ESI): 413; M+ (ESI): 415. HPLC, Rt: 3.09 min (purity: 97.6%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[CH3:44][C:45]1[CH:49]=[C:48]([CH2:50][C:51](O)=[O:52])[O:47][N:46]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:51](=[O:52])[CH2:50][C:48]3[O:47][N:46]=[C:45]([CH3:44])[CH:49]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cc(CC(=O)O)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1cc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)on1
Reaction time: 0.17 h
Yield: 88.6 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3-methyl-5-isoxazoleacetic acid (0.3 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH: CH2Cl2 5:95) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-methyl-isoxazol-5-yl)-acetamide (0.8 g, 84%) as a white solid: mp 179-181° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=1.71 min. (97%); 1H NMR (DMSO-d6) δ 2.04-2.09 (m, 1H), 2.20 (s, 3H), 2.53-2.63 (m, 2H), 2.84-2.92 (m, 1H), 3.77 (s, 2H), 4.73 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 6.21 (s, 1H), 7.69-7.87 (m, 3H), 8.80 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 10.91, 21.95, 30.90, 33.46, 38.00, 48.85, 103.79, 121.99, 127.18, 131.54, 133.27, 134.75, 138.66, 159.51, 166.85, 166.90, 167.41, 169.77, 172.72; Anal. Calcd. for C20H18N4O6: C, 58.54; H, 4.42; N, 13.65. Found: C, 58.18; H, 4.19; N, 13.52.