Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([N:11]1[C:19]2[C:14](=[C:15]([CH2:20][N:21]3[C:27](=[O:28])[C@@H:26]([NH:29][C:30](=[O:42])[C@@H:31]([N:33]([CH3:41])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:32])[CH2:25][O:24][C:23]4[CH:43]=[CH:44][CH:45]=[CH:46][C:22]3=4)[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)[CH3:10]>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:1][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]2[C:27](=[O:28])[C@@H:26]([NH:29][C:30](=[O:42])[C@@H:31]([N:33]([CH3:41])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:32])[CH2:25][O:24][C:23]3[CH:43]=[CH:44][CH:45]=[CH:46][C:22]2=3)[N:11]([CH2:9][CH3:10])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCn1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc4ccccc43)cccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(Cl)c2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc4ccccc43)cccc21
Yield: 90.8 %

Procedure:
A solution of N-chlorosuccinimide (NCS, 17.2 mg, 129 μmol, Eq: 1.00) in DMF (2 mL) was added dropwise to a solution of tert-butyl (S)-1-((S)-5-((1-ethyl-1H-indol-4-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (67 mg, 129 μmol, Eq: 1.00) in DMF (12 mL) at 0° C. After 2 h at 0° C. the mixture was diluted with sat. NaHCO3 and extracted with EtOAc. The combined extracts were washed with H2O, concentrated and the residue was purified by preparative TLC to give tert-butyl (S)-1-((S)-5-((3-chloro-1-ethyl-1H-indol-4-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (65 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([S:13](Cl)(=[O:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([S:13](=[O:15])(=[O:14])[NH:20][CH2:19][CH2:17][OH:18])[N:12]=2)=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1c[nH]c(-c2ccc(Cl)cc2)n1
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(NCCO)c1c[nH]c(-c2ccc(Cl)cc2)n1
Yield: 20 %

Procedure:
To a solution of 2-(4-chlorophenyl)-4-chlorosulfonylimidazole (1.3 g 0.005 m) in dioxane (15 ml) was added ethanolamine (0.61 g 0.01 ml). After 15 minutes the dioxane was removed under reduced pressure (20 mm) to yield a gum. The gum was slurried with water to yield a solid. The solid was filtered and recrystallized from acetonitrile to give 400 mg of 2-(4-chlorophenyl)-4-(2-hydroxyethylsulfamoyl)imidazolemelting at 210°-212°. (20% yield).
Reaction SMILES: C(N)C1C=CC=CC=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1.[F:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][N:37]=3)[C:31](OC)=[O:32])[C:24]2=[O:38])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][N:37]=3)[C:31]([NH:16][CH2:15][C:11]3[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=3)=[O:32])[C:24]2=[O:38])=[CH:39][CH:40]=1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: NCc1cccnc1
Solvent: NCc1ccccc1
Product: O=C(NCc1cccnc1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 39 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with pyridin-3-ylmethanamine to react with methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-3-ylmethyl)isonicotinamide was obtained as a colorless solid in 39% yield: mp 153-155° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.29 (br, 1H), 8.60 (s, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.44-8.42 (m, 1H), 8.37 (d, J=5.4 Hz, 1H), 7.71-7.68 (m, 1H), 7.35-7.31 (m, 4H), 7.18-7.13 (m, 2H), 4.46 (d, J=6.0 Hz, 2H), 4.39 (s, 2H), 3.93 (t, J=7.5 Hz, 2H), 3.38-3.34 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 165.8, 156.8, 153.5, 149.3, 148.7, 148.5, 143.2, 135.7, 135.1, 133.6, 133.6, 130.4, 130.3, 124.0, 116.0, 115.7, 115.2, 110.4, 46.6, 41.6, 41.2, 41.0; MS (ES+) m/z 406.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][NH2:10])=[N:4][CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)CC)C.[F:18][C:19]([F:25])([F:24])[CH2:20][C:21](Cl)=[O:22].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:9][NH:10][C:21](=[O:22])[CH2:20][C:19]([F:25])([F:24])[F:18])=[N:4][CH:5]=[CH:6][C:7]=1[I:8]
Reactant: O=C(Cl)CC(F)(F)F
Reactant: NNc1nccc(I)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CC(F)(F)F)NNc1nccc(I)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of intermediate compound D7 (2.528 g, 9.38 mmol) in dry DCM (15 ml), cooled at 0° C., were added triethylamine (3.244 ml, 23.45 mmol) and 3,3,3,-trifluoropropionyl chloride (1.924 g, 13.132 mmol). The resulting reaction mixture was stirred at r.t. for 3 h. After this period, NaHCO3 (aqueous sat. solution) was added. The resulting solution was then extracted with DCM. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residue thus obtained was triturated with DIPE to yield intermediate compound D10 (4 g, 55%).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:10](=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](O)[CH:8]=2)[N:3]1[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:28]1.Br[CH2:48][C:49]([O:51][CH3:52])=[O:50]>>[O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10](=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:48][C:49]([O:51][CH3:52])=[O:50])[CH:8]=2)[N:3]1[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH:34]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)CCCCn1c(=O)c2cc(O)ccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Reactant: COC(=O)CBr
Product: COC(=O)Cc1ccc2c(c1)c(=O)n(CCCCC(=O)O)c(=O)n2CCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 72.2 %

Procedure:
Using the method similar to that in Example 106 and starting from ethyl 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-6-hydroxy-1,2,3,4-tetrahydroquinazoline-3-valerate (1.31 g, 2.09 mmol) obtained in Example 105, and also using methyl bromoacetate (237 ml, 2.50 mmol) instead of benzyl bromide, the ethyl ester of the title compound (990 mg, 68%) was obtained as an oil.
Reaction SMILES: C([N:11]1[CH2:29][CH2:28][CH2:27][C@H:12]1[C:13]([NH:15][C:16]([C:24]([OH:26])=[O:25])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])(OCC1C=CC=CC=1)=O.CCOCC.[BrH:35].CC(O)=O>>[BrH:35].[NH:11]1[CH2:29][CH2:28][CH2:27][C@H:12]1[C:13]([NH:15][C:16]([C:24]([OH:26])=[O:25])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14]
Reactant: O=C(O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1
Yield: 74 %

Procedure:
A solution of 0.5 g (0.00125 mole) of N-carbobenzoxy-L-prolyl-dehydrophenylalanine in 3 ml of 32% HBr/HOAc was treated as N-carbobenzoxy-L-prolyl-dehydrophenylalanine azlactone was treated in Example 7(a) except that the ether precipitated product was allowed to stand two days at room temperature before filtration and crystallization from methanol/ethyl acetate to yield 0.313 g (74%) of L-prolyl-dehydrophenylalanine hydrobromide, m.p. 227°-228.5° (dec.), RfA 0.45.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[N+](=[CH2:23])=[N-]>CO.CCOCC>[CH3:23][O:18][C:7]1[CH2:8][C:9](=[O:17])[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]2[CH:3]=[C:2]([Cl:1])[CH:20]=[CH:19][C:5]=2[N:6]=1
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Reaction time: 1 h

Procedure:
To 11.4 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione stirred in 150 ml methanol is added, dropwise, approximately 2.1 g of diazomethane in ether. After addition is complete, the reaction is stirred for 1 hour and filtered. The filtrate is evaporated and the residue diluted with a small amount of ether. The suspension is filtered and the filtrate evaporated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][F:10])=[CH:4][CH:3]=1.O1CCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:27][C:28]([F:37])([F:36])[C:29](N1C=CN=C1)=[O:30].Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH:9]([F:10])[C:29](=[O:30])[C:28]([F:37])([F:36])[F:27])=[CH:6][CH:7]=1
Reactant: O=C(CF)c1ccc(Br)cc1
Reactant: O=C(n1ccnc1)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)C(F)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 101.9 %

Procedure:
To a solution of 1-(4-bromophenyl)-2-fluoro-1-ethanone (3.54 g, 16.3 mmol) in tetrahydrofuran (50 ml) was added dropwise 1M lithium hexamethyldisilazide tetrahydrofuran solution (19.6 ml, 19.6 mmol) at −78° C. After stirring for 45 min., N-trifluoroacetylimidazole (2.3 ml, 19.6 mmol) was added. The resulting mixture was allowed to warm up to room temperature and stirred for 1.5 hr. The mixture was acidified with 2M hydrochloric acid and extracted with diethyl ether (300 ml). The separated organic layer was washed with water (100 ml×3) and dried over magnesium sulfate. The solution was evaporated to give 5.2 g of 1-(4-bromophenyl)-2,4,4,4-tetrafluoro-1,3-butanedione as a brown oil. This residue was heated with 5-hydrazino-2-pyrisinesulfonamide hydrochloride (1.10 g, 4.89 mmol) at refluxing temperature for 18 hr. After evaporation, the obtained residue was chromatographed on a column of silica gel (500 g) eluting with ethyl acetate/hexane (1:3 to 1:1) to afford 930 mg (12%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]2[O:36][C:35]([C:37]3[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=3[F:44])=[N:34][C:33]=2[C:45]#[N:46])=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:45]([C:33]1[N:34]=[C:35]([C:37]2[C:38]([F:44])=[CH:39][CH:40]=[CH:41][C:42]=2[F:43])[O:36][C:32]=1[NH:31][C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:11](=[O:13])[CH2:10][CH2:9][N:8]([CH3:14])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:30][CH:29]=1)#[N:46]
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Nc1ccc(N)cc1
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCC(=O)Nc1ccc(Nc2oc(-c3c(F)cccc3F)nc2C#N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-3-methylaminopropanoic acid (0.022 g, 0.11 mmol) in DMF (1.25 ml) were added O-(7-azabenzotriazol-1-yl)-N,N,N′,N1-tetramethyluronium hexafluorophosphate (0.040 g, 0.11 mmol) and diisopropylethylamine (0.018 ml, 0.11 mmol) followed by 5-(4-aminophenylamino)-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (0.030 g, 0.10 mmol) and the resultant mixture stirred at room temperature overnight. A further portion of N-(tert-butoxycarbonyl)-3-methylaminopropanoic acid (0.022 g, 0.11 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.040 g, 0.11 mmol) and diisopropylethylamine (0.018 ml, 0.11 mmol) was added and the reaction stirred for 2 hours at room temperature. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford tert-butyl 3-(4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)phenylamino)-3-oxopropyl(methyl)carbamate (0.021 g, 0.04 mmol, 44%) as a white solid. LCMS (2) Rt: 3.03 min; m/z (ES+) 498.
Reaction SMILES: [Br-].[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Zn+])#[N:3].[Cu](C#N)C#N.[Br-].[Li+].[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22](Cl)=[O:23]>O1CCCC1>[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:2]#[N:3])=[O:23]
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Reactant: N#Cc1ccccc1[Zn+]
Agent: N#C[Cu]C#N
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccccc1C(=O)c1ccc(F)c(Br)c1
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
To a −20° C. solution of 2-cyanophenylzinc bromide (0.5 M in tetrahydrofuran, 20 mL, 10 mmol) was a solution of copper cyanide (0.94 g, 10.5 mmol) and lithium bromide (1.82 g, 21.0 mmol) in tetrahydrofuran (15 mL) added, the reaction was slowly allowed to reach room temperature, after 15 minutes the reaction mixture was recooled to −25° C. A solution of 3-bromo-4-fluorobenzoyl chloride (1.45 g, 10.5 mmol) in tetrahydrofuran (10 mL) was added, the reaction mixture was stirred at −25° C. 1 h and at room temperature over night. After partition between aqueous ammonium chloride and diethylether, the organic phase was dried over magnesium sulfate and concentrated to give the crude title product which was used without further purification. MS (ESI) m/z 304, 306 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11][CH:10]([O:13][P:14](Cl)Cl)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>>[C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11][CH:10]([O:13][P:14]([C:24]3[NH:23][CH:27]=[CH:26][N:25]=3)[C:24]3[NH:23][CH:27]=[CH:26][N:25]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1c[nH]cn1
Reactant: ClP(Cl)OC1CCC(c2ccccc2)(c2ccccc2)CC1
Product: c1ccc(C2(c3ccccc3)CCC(OP(c3ncc[nH]3)c3ncc[nH]3)CC2)cc1

Procedure:
A process for preparing (4,4-diphenylcyclohexyl)phosphooxymethyl diethylene triaminepenta-acetic acid comprising the steps of: (a) phosphorylating 1.0 equivalents of 4,4-diphenylcyclohexanol with about one equivalent of phosphorous trichloride to obtain 4,4-diphenylcyclohexyloxy dichlorophosphine having the formula: ##STR20## (b) coupling the 4,4-diphenylcyclohexyloxy-dichlorophosphine formed in step (a) with from about 5 to about 6 equivalents of imidazole to obtain 4,4-diphenycyclohexyloxy-diimidazolylphosphine having the formula: ##STR21## where imido refers to imidazolyl (c) coupling of the 4,4-diphenylcyclohexyloxy- diimidazolylphosphine formed in step (b) with from about 0.75 to about 1.0 equivalents of hydroxymethyl-DTPA penta tert-butyl ester to obtain 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA -oxy, penta tert-butyl ester) imidazolyl-phosphine having the formula: ##STR22## where imido refers to imidazolyl (d) hydrolysis and oxidation of the 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA oxy, penta tert butyl ester) imidazolylphosphine formed in step (c) with dilute HCl and from about 0.5 to about 2.0 equivalents to sodium periodate to form (4,4-diphenylcyclohexyl)phosphonooxymethyl diethylene triamine, penta t-butyl ester having the formula: ##STR23##
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:20]([O:24][C:25]([N:27]1[CH2:28][CH:29]=[C:30]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:31][CH2:32]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1ccc(Nc2nc3c(Br)cccn3n2)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1ccc(Nc2nc3c(C4=CCN(C(=O)OC(C)(C)C)CC4)cccn3n2)cc1

Procedure:
4-[2-(4-Methoxy-phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(4-methoxy-phenyl)-amine (150.0 mg, 0.4700 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (160.0 mg, 0.5174 mmol) with Pd(dppf)Cl2 (0.035 g) as the catalyst in a manner analogous to Step 19e. The reaction product was isolated as a clear viscous oil. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.30 (dd, J=6.6, 1.0 Hz, 1H), 7.52-7.47 (m, 2H), 7.33-7.29 (m, 1H), 7.25-7.20 (m, 1H), 6.94-6.89 (m, 2H), 6.84 (dd, J=7.3, 7.3 Hz, 1H), 6.63 (s, 1H), 4.23-4.19 (m, 2H), 3.81 (s, 3H), 3.73-3.67 (m, 2H), 2.69-2.62 (m, 2H), 1.50 (s, 9H). MS=422 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1C1(N)CCCCC1)[C:5]([O:7]CC)=[O:6].OOS([O-])=O.[K+].[O:26]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27]1.[OH-].[Na+]>CN(C=O)C.O>[CH:2]1([N:1]2[C:12]3[CH:11]=[CH:10][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=3[N:1]=[C:31]2[C:28]2[CH:29]=[CH:30][O:26][CH:27]=2)[CH2:3][CH2:4][CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)c1ccc(C2(N)CCCCC2)c(N)c1
Reactant: O=Cc1ccoc1
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 170 %

Procedure:
Ethyl 3-amino-4-(aminocyclohexyl)benzoate (3.67 g, 13.99 mmol) was dissolved in DMF (10 mL) and water (1 mL). Oxone® (9. 8 mmol, 6.02 g) was added followed by 3-furaldehyde (1.44 g, 15 mmol). The mixture was stirred 45 min at room temperature. 4 N NaOH (20 mL) was added and the mixture stirred at 60° C. for 18 h. After cooling to room temperature, water (100 mL) was added and insoluble impurities removed by filtration through celite. AcOH was then added to precipitate the product as a beige solid. The precipitated carboxylic acid was collected by filtration, washed with water and dried to give the title compound as a beige solid (3.69 g, 85% yield).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([F:13])=[CH:10][C:9]=2[CH:14]=1.Cl.[O:16]1CCC[CH2:17]1>[Cl-].[Na+].O.CN(C)C=O>[F:13][C:11]1[O:12][C:8]2[CH:7]=[CH:6][C:5]([CH:17]=[O:16])=[CH:14][C:9]=2[CH:10]=1
Reactant: Fc1cc2cc(Br)ccc2o1
Reactant: C1CCOC1
Agent: Cl
Agent: II
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc2oc(F)cc2c1

Procedure:
A slurry of magnesium powder (219 mg) and iodine (cat) in dry tetrahydrofuran (3 ml) was heated at 50° C. under nitrogen for 20 minutes. 5-Bromo-2-fluoro-1-benzofuran (1.4 g) was dissolved in dry tetrahydrofuran (6 ml). A 1 ml portion of the solution was added to the slurry at 50° C. without stirring. After 30 minutes the rest of the solution was added slowly and the reaction was heated at reflux for 3 hours. The reaction was cooled in an ice/water bath and dimethylformamide (1 ml) was added dropwise maintaining the temperature below 10° C. After 1 hour a mixture of 2N hydrochloric acid (12.5 ml) and brine (12.5 ml) was added. The reaction mixture was extracted using ethyl acetate (3×25 ml). The combined organics were washed with brine and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue applied to a silica cartridge (50 g). This was eluted with cyclohexane, cyclohexane/ethyl acetate (6:1, 5:1 v/v). This gave 2-fluoro-5-formyl-1-benzofuran (376 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.CN.Cl.[CH3:15][N:16](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1.CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:16][CH3:15])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)Cc1cccc(Br)c1
Yield: 40.6 %

Procedure:
A mixture of 3-bromophenylacetic acid (3.02 g), a solution (2.0 M; 8.5 ml) of methylamine in THF, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.20 g), 1-hydroxybenzotriazole (2.60 g) and triethylamine (2.3 ml) was stirred in DMF (30 ml) at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate, washed successively with water, 1N aqueous sodium hydroxide solution, 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chomatography (eluent; ethyl acetate). Recrystallization from hexane-ethyl acetate gave the title compound (1.30 g) as colorless prism crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][CH:19]([F:36])[C:20]([C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])=[CH:24][CH:23]=1)=[O:21]>>[F:36][CH:19]([F:18])[C:20]([C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:15][CH2:14][C:13]([C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][CH:10]=2)([CH3:17])[CH3:16])=[O:31])=[CH:24][CH:23]=1)=[O:21]
Reactant: O=C(O)c1cccc(-c2ccc(C(=O)C(F)F)s2)c1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Product: CC(C)(CNC(=O)c1cccc(-c2ccc(C(=O)C(F)F)s2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 34 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(5-(2,2-difluoroacetyl)thiophen-2-yl)benzoic acid as described in example 8 step 6 (60 mg, yield 34%). 1H NMR (400 MHz, DMSO-d6) δ 8.51-8.48 (t, J=6.2 Hz, 1H), 8.19-8.15 (m, 2H), 8.02-7.97 (m, 3H), 7.90-7.88 (m, 1H), 7.84-7.83 (d, J=4.3 Hz, 1H), 7.61-7.57 (t, J=7.8 Hz, 1H), 7.35-7.31 (t, J=8.8 Hz, 2H), 7.16-6.90 (m, 1H), 3.52-3.50 (d, J=6.4 Hz, 2H), 1.29 (s, 6H). MS (ESI) m/z: Calculated for C26H21F3N2O3S: 498.12. found: 499.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][C:15]([CH3:32])([C:17]2[O:21][N:20]=[C:19]([NH:22]C(OC3C=CC=CC=3)=O)[CH:18]=2)[CH3:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O-2].[Mg+2].O1CCOCC1>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][C:15]([C:17]2[O:21][N:20]=[C:19]([NH2:22])[CH:18]=2)([CH3:16])[CH3:32])(=[O:11])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(COS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1cc(NC(=O)Oc2ccccc2)no1
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(COS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1cc(N)no1
Temperature: 60 °C
Reaction time: 5 h
Yield: 87.9 %

Procedure:
A stirred mixture of 2-methyl-2-(3-(phenoxycarbonylamino)isoxazol-5-yl)propyl 4-nitrobenzenesulfonate (130 mg, 0.22 mmol), magnesium oxide (45 mg, 0.87 mmol), 1,4-dioxane (8 mL) and water (2 mL) was stirred at 60° C. for 5 h. The reaction mixture was cooled to rt and filtrated. The filtrate was concentrated under reduced pressure to give the crude product. Purification via recrystallization from a 1:1 mixture of diethyl ether and hexane, afforded 2-(3-aminoisoxazol-5-yl)-2-methylpropyl 4-nitrobenzenesulfonate (66 mg, 69%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) 88.38-8.40 (m, 2H), 7.99-8.00 (m, 2H), 5.55 (s, 1H), 4.13 (s, 2H), 1.32 (s, 6H).