Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)N1CCOCC1)C(OCC)=O)#N.[C:44]([C:46]1[N:47]=[C:48]([C:59]2[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH3:67])=[C:61]([C:68]([F:71])([F:70])[F:69])[CH:60]=2)[C:49]2[CH:54]=[CH:53][N:52]([CH2:55][C:56](O)=[O:57])[C:50]=2[N:51]=1)#[N:45]>O.CN(C=O)C>[CH2:66]([O:65][C:62]1[CH:63]=[CH:64][C:59]([C:48]2[C:49]3[CH:54]=[CH:53][N:52]([CH2:55][C:56]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[O:57])[C:50]=3[N:51]=[C:46]([C:44]#[N:45])[N:47]=2)=[CH:60][C:61]=1[C:68]([F:69])([F:70])[F:71])[CH3:67]
Reactant: CN1CCNCC1
Reactant: CCOc1ccc(-c2nc(C#N)nc3c2ccn3CC(=O)O)cc1C(F)(F)F
Agent: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(C#N)nc3c2ccn3CC(=O)N2CCN(C)CC2)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
1-Methylpiperazine (42 μL), N,N-diisopropylethylamine (66 μL), and (1-cyano-2-ethoxy-2-oxoethylidene aminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (187 mg) were added to a mixture of {2-cyano-4-[4-ethoxy-3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}acetic acid (100 mg) and DMF (4 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. After water was added to the reaction mixture, the precipitate was collected by filtration, and washed with water. After the obtained solid was dissolved in CHCl3, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH=100:0 to 50:50), whereby 4-[4-ethoxy-3-(trifluoromethyl)phenyl]-7-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (82 mg) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH2:11])[CH2:5]2.C(N(C(C)C)CC)(C)C.Cl[CH2:22][CH2:23][C:24]1[CH:32]=[C:31]([O:33][CH2:34][C@@H:35]2[CH2:39][CH2:38][CH2:37][O:36]2)[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].CC(C)([O-])C.[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([N:11]1[CH2:22][CH2:23][C:24]3[C:25](=[CH:29][CH:30]=[C:31]([O:33][CH2:34][C@@H:35]4[CH2:39][CH2:38][CH2:37][O:36]4)[CH:32]=3)[C:26]1=[O:27])[CH2:5]2
Reactant: N[C@@H]1Cc2ccc(Br)cc2C1
Reactant: O=C(Cl)c1ccc(OC[C@@H]2CCCO2)cc1CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1c2ccc(OC[C@@H]3CCCO3)cc2CCN1[C@@H]1Cc2ccc(Br)cc2C1
Reaction time: 0.08 h

Procedure:
A mixture of (R)-5-bromoindan-2-ylamine (hydrochloride, 1.05 g), THF (20 ml) and diisopropylethylamine (1.0 g) was admixed with 2-(2-chloroethyl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzoyl chloride (1.28 g; from 6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]-isochroman-1-one by boiling with thionyl chloride). After 5 minutes, potassium tert-butoxide (1.42 g) was added. After 12 hours, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel (eluent: 1:1 ethyl acetate/heptane). This afforded the product with the molecular weight of 442.36 (C23H24BrNO3); MS (ESI): 442 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:18]([C:19]3[C:20](=O)[NH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=3)[C:10]3[N:11]=[C:12]([CH3:17])[N:13]([CH:14]4[CH2:16][CH2:15]4)[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:28]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:18]([C:19]3[C:20](=[S:38])[NH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=3)[C:10]3[N:11]=[C:12]([CH3:17])[N:13]([CH:14]4[CH2:16][CH2:15]4)[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:28]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1nc2c(n1C1CC1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O
Solvent: C1COCCO1
Product: Cc1nc2c(n1C1CC1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
A mixture of the product of step (i) (0.070 g) and Lawesson's reagent (0.350 g) in 1,4-dioxane (5 ml) was heated at reflux for 8 hours. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane and water. Purification was by chromatography eluting with 0.2% 880 ammonia, 2% methanol in dichloromethane to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[Br:13]Br>C(Cl)Cl>[Br:13][CH2:11][C:10]([C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:12]
Reactant: CC(=O)c1cc(F)c(F)cc1F
Reactant: BrBr
Solvent: ClCCl
Product: O=C(CBr)c1cc(F)c(F)cc1F
Temperature: 23 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A 1 L 3-neck round bottom flask was charged with 1-(2,4,5-trifluorophenyl)ethanone (49.7 g, 285 mmol) and DCM (350 mL). The flask was equipped with a 250 mL dropping funnel that contained a solution of bromine (14.6 mL, 283 mmol) in DCM (125 mL). This solution was added to the reaction flask over about 1 h at about 23° C. Once addition of the solution was complete, the reaction mixture was stirred for about 1 h at about 23° C. Ice water was added to the reaction flask and the layers were stirred for about 15 min. The layers were separated and the organic solution was then washed with water and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a pale yellow solid (70.3 g, 97%): LC/MS (Table 1, Method b) Rt=2.20 min; MS m/z 251.0/253.0 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[N:5][CH:4]=[C:3]1[C:17]([O:19]CC)=O.[NH3:22]>>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[N:5][CH:4]=[C:3]1[C:17]([NH2:22])=[O:19]
Reactant: N
Reactant: CCOC(=O)c1cnc(-c2ccccc2OCC)[nH]c1=O
Product: CCOc1ccccc1-c1ncc(C(N)=O)c(=O)[nH]1
Yield: 77 %

Procedure:
A mixture of ethyl 1,6-dihydro-6-oxo-2-(2-ethoxyphenyl)pyrimidine-5-carboxylate (10.0 g.) and aqueous ammonia (120 ml., d = 0.90) was heated in a sealed vessel on a steam bath for 4.5 hours. The solution was partially evaporated and then acidified to pH 3 with 6N hydrochloric acid. The collected solid was washed with water, dried, and recrystallized from N,N-dimethylformamide to give the title compound (6.93 g., 77% yield), m.p. 236°-238°.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[CH:12]=[C:11]2[S:20](Cl)(=[O:22])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[CH:12]=[C:11]2[S:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)(=[O:22])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2n1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Product: O=S(=O)(c1cc2ccc(Cl)cc2n1S(=O)(=O)c1ccccc1)N1CCNCC1
Reaction time: 4 h
Yield: 65.4 %

Procedure:
The requisite 1-(1-benzenesulphonyl-6-chloroindol-2-ylsulphonyl)piperazine starting material was prepared as follows. A solution of 1-benzene sulphonyl-6-chloroindol-2-ylsulphonyl chloride (5.0 g, 12.8 mmol) in dichloromethane (50 ml) was added dropwise to a stirred solution of piperazine (6.62 g, 6 eq.) in dichloromethane (100 ml), and the mixture stirred for a further 4 hrs. giving a yellow solution. This was then evaporated and dried overnight under high vacuum. The residue was purified by flash chromatography using Merck silica (Art. 9385), eluting with dichloromethane containing methanol (06%), to give 1-(1-benzenesulphonyl-6-chloroindol-2-ylsulphonyl)piperazine as an off-white solid (3.68 g, 68% yield); 1H NMR (CDCl3) 2.75 ppm (m, 4H), 3.3 ppm (m, 4H), 7.45 ppm (d, 1H), 7.6 ppm (m, 3H), 7.7 ppm (m, 1H), 7.75 ppm (d, 1H), 8.0 ppm (d, 2H), 8.15 ppm (s, 1H); MS (M+H)+ 440/442.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[F:20][C:21]1([F:32])[CH2:24][N:23]([C:25](=[O:31])[C:26]([OH:30])([CH3:29])[C:27]#[CH:28])[CH2:22]1>>[F:32][C:21]1([F:20])[CH2:24][N:23]([C:25](=[O:31])[C:26]([OH:30])([CH3:29])[C:27]#[C:28][C:2]2[C:3]([F:19])=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:18]=2)[CH2:22]1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)C(=O)N1CC(F)(F)C1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C(=O)N1CC(F)(F)C1
Yield: 5 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 1-(3,3-difluoroazetidin-1-yl)-2-hydroxy-2-methylbut-3-yn-1-one to give the titled compound as an off-white solid (14 mg, 5%).
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[O:11][CH:12]=[C:13]([CH:15]([OH:17])[CH3:16])[N:14]=1)([CH3:6])([CH3:5])[CH3:4]>C(C#N)(C)=O.O=[Mn]=O>[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[O:11][CH:12]=[C:13]([C:15](=[O:17])[CH3:16])[N:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(O)c1coc(C(C)(C)O[SiH2]C(C)(C)C)n1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1coc(C(C)(C)O[SiH2]C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-yl]-ethanol (193 mg, 0.75 mmol) in AcCN (5.0 mL) was treated at rt with MnO2 (362 mg, 3.75 mmol). The reaction mixture was stirred for 16 h at rt before being filtered through Celite. The solvent was removed under reduced pressure to give the title compound as a white solid. TLC:rf (1:1 hept-EA)=0.69. LC-MS-conditions 02: tR=1.04 min, [M+H]+=255.84.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[N:13]=[C:12]2[CH:22]([CH3:24])[CH3:23])=[CH:6][CH:5]=1>ClCCl.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[C:15]3[CH:16]([OH:21])[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[N:13]=[C:12]2[CH:22]([CH3:24])[CH3:23])=[CH:8][CH:9]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CCCC2
Reaction time: 1 h
Yield: 89 %

Procedure:
Sodium borohydride (100 mg) was added to a stirred solution of Intermediate 3 (420 mg) in dichloromethane (3 ml) and methanol (3.00 ml). The reaction mixture was stirred for 1 hour. The reaction mixture was partitioned between EtOAc (50 ml) and water (30 ml). The two phases were separated and the aqueous phase was extracted again with EtOAc (30 ml). The phases were separated, the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum to give the title compound (376 mg). LC/MS MH+ 319, Rt 0.77 min (2 minute run).
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH3:9][C:10](=[CH:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:11]>C(#N)C.C1(NN)C=CC=CC=1>[CH3:8][CH2:7][O:6][C:4]([CH:3]1[C:14]([CH3:16])([CH3:15])[CH:13]1[CH:12]=[C:10]([CH3:11])[CH3:9])=[O:5]
Reactant: CC(C)=CC=C(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: CC#N
Solvent: NNc1ccccc1
Product: CCOC(=O)C1C(C=C(C)C)C1(C)C
Temperature: 50 °C
Reaction time: 6 h
Yield: 50.9 %

Procedure:
0.2 g of the catalyst whose preparation is described in example 44 are suspended in 3 ml of acetonitrile then 0.096 mmol (0.01 g) of phenylhydrazine in 3 ml of acetonitrile are added. The reaction mixture is heated to 50° C. and 0.1 ml of a solution containing 0.21 ml (2 mmol) of ethyl diazoacetate in 3 ml acetonitrile is added. 10 mmol of 2,5-dimethyl-2,4-hexadiene (1.4 ml) are then added, followed by the remaining 2.9 ml of the ethyl diazoacetate solution in acetonitrile, added over a period of about 1 hour. The reaction mixture is maintained under stirring at 50° C. for 6 hours. The catalyst is removed by filtration and washed with 20 ml of dichloromethane. 0.2 g of ethyl chrysanthemate are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:45][CH3:46])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:21][N:20]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].[Li+].[OH-].C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:45][CH3:46])[C:12]([NH:17][C@H:18]2[C@@H:22]([OH:23])[CH2:21][N:20]([C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Reaction time: 0.75 h
Yield: 49.8 %

Procedure:
To a solution of benzyl (cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-[(4-nitrobenzoyl)oxy]pyrrolidine-1-carboxylate (3.17 g) in tetrahydofuran (38 ml) and methanol (3 ml) was added LiOH (1M(aq), 38 ml). The reaction mixture stirred 45 min and was poured into saturated sodium bicarbonate (100 ml). The aqueous layer was extracted ethyl acetate (2×200 ml), dried MgSO4, filtered and concentrated. MPLC chromatography on a biotage 40M column with 20-60% ethyl acetate/heptane provided the title compound as an oil (1.225 g, 50%): 1H NMR (400 MHz, CDCl3) δ) 7.50, 7.46-7.25, 5.18, 4.99, 4.89, 4.70, 4.51, 4.04, 3.75-3.59, 3.42-3.35, 2.70, 2.47, 2.19, 1.14; HRMS (FAB) calcd for C26H28Cl2N4O3+H 515.1616, found 515.1641. Anal. Calcd for C26H28Cl2N4O3: C, 60.59; H, 5.48; N, 10.87. Found: C, 60.32; H, 5.79; N, 10.54.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C@H:10]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[C:23]5[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:22]=5[S:21][CH:20]=4)[CH2:15][C@H:14]3[CH3:30])[O:9][CH2:8][CH2:7][C:6]=2[CH:31]=1.[NH:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:28]([C:26]1[CH:25]=[CH:24][C:23]2[C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C@H:10]4[C:5]5[CH:4]=[CH:3][C:2]([N:32]6[CH2:36][CH2:35][NH:34][C:33]6=[O:37])=[CH:31][C:6]=5[CH2:7][CH2:8][O:9]4)[C@H:14]([CH3:30])[CH2:15]3)=[CH:20][S:21][C:22]=2[CH:27]=1)#[N:29]
Reactant: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1CC[C@@H]1OCCc2cc(Br)ccc21
Reactant: O=C1NCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1CC[C@@H]1OCCc2cc(N3CCNC3=O)ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-((3R)-4-{2-[(1S)-6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}-3-methylpiperazinyl)-1-benzothiophene-6-carbonitrile (0.36 g, 0.73 mmol)was dissolved in dry toluene (15 mL) and degassed. 2-Imidazolidinone (0.071 g, 0.82 mmol), tris(dibenzylideneacetone)dipalladium (34 mg), (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (47 mg) and caesium carbonate (0.34 g, 1.05 mmol)were added and the mixture heated under reflux with stirring, under a nitrogen atmosphere, for 2 days. The reaction was cooled to room temperature, diluted with dichloromethane, filtered through celite and washed with water. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo. Purification by LC-MS yielded the title compound as the free base. M+H=502.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:25](=[O:26])[C:24]4[CH:28]=[CH:29][CH:30]=[C:22]([O:21][C:20]([F:19])([F:31])[F:32])[CH:23]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cccc(OC(F)(F)F)c1
Yield: 64 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-(trifluoromethoxy)benzoyl chloride to afford the title compound as an off-white solid (36 mg, 64%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=6.0 Hz), 6.93 (d, 1H, Harom, J=7.0 Hz), 7.44 (ps t, 1H, Harom, J=8.0 Hz), 7.62 (s, 1H, Harom), 7.64-7.69 (m, 3H, Harom), 7.81 (d, 1H, HPy,6, J=6.0 Hz), 7.88 (s, 1H, Harom), 7.99 (d, 1H, Harom, J=8.0 Hz), 10.47 (s, 1H, NHamide), 11.20 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). 13C-NMR (δ, ppm, DMSO-d6): 106.61, 110.86, 113.78, 114.72, 116.36, 120.05, 121.07, 124.17, 126.80, 130.23, 130.64, 136.83, 140.47, 141.35, 144.55, 147.17, 148.28, 154.21, 154.76, 164.03. HRMS (EI): m/z [M+H] calcd for C20H14F3N4O4: 431.0967; found: 431.0968.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]([O:20][N:21]=[C:22](C)[CH3:23])=[C:7](C(=O)C)[N:6]=1)=[O:4]>CO.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[C:22]([CH3:23])=[N:21][O:20][C:8]2=[C:9]([F:19])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[O:4]
Reactant: COC(=O)c1nc(C(C)=O)c(ON=C(C)C)c(F)c1Nc1ccccc1F
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1nc2c(C)noc2c(F)c1Nc1ccccc1F
Reaction time: 1 h

Procedure:
To a solution of acetone oxime (2.20 equivalents) at room temperature is added t-BuOK (2.20 equivalents, 1.0 M solution in THF). After stirring for 30 minutes room temperature, the reaction mixture is cooled to 0° C. A solution 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (1.00 equivalent) in THF is added. After stirring for 1 hour at 0-5° C., the reaction mixture is quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4, concentrated in vacuo to give 6-acetyl-4-fluoro-3-(2-fluorophenylamino)-5-isopropylideneaminooxy-pyridine-2-carboxylic acid methyl ester that is used directly. A mixture of 6-acetyl-4-fluoro-3-(2-fluorophenylamino)-5-isopropylideneaminooxy-pyridine-2-carboxylic acid methyl ester in 5% aqueous MeOH is refluxed with stirring for 1 hour. The reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by flash column chromatography to afford the desired product.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[Br:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][NH:5][C:4]2=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)NCCc1ccc(Br)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2ccc(Br)cc21
Yield: 12033.2 %

Procedure:
Using analogous reaction conditions and workup as described in Example 1, step 4, [2-(4-bromo-phenyl)-ethyl]-carbamic acid ethyl ester (I-3c: 5 g, 0.01838 mmol) in POCl3 (20 mL) was reacted with P2O5 (5.2 g, 0.03676 mmol) to afford the crude product. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 500 mg of the product (12% yield).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Br:21]>C1(C)C=CC=CC=1>[Br:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH2:13][OH:12]
Reactant: COC(=O)c1ccc(Cl)cc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1ccc(Cl)cc1Br
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A 1.0 M solution of diisobutylaluminum hydride in toluene (43 mL, 0.043 mol) was added slowly drop-wise to a −78° C. solution of 2-bromo-4-chloro-benzoic acid methyl ester (10.57 g, 0.042 mol) in toluene (50 mL) and hexanes (425 mL). The reaction mixture was stirred at −78° C. for 1.5 hours. After this time, a white solid had precipitated out of solution. The reaction mixture was quenched at −78° C. with ethyl acetate (100 mL). Saturated aqueous sodium potassium tartrate was added, and the reaction mixture was warmed to room temperature. The organic phase was separated, dried over Na2SO4, filtered, and concentrated to a clear oil. TLC (30% ethyl acetate/hexanes) and 1H NMR revealed a mixture with unreacted 2-bromo-4-chloro-benzoic acid methyl ester as the major component. The crude material was dissolved in toluene (300 mL), and the resulting solution was cooled to −78° C. A 1.0 M solution of diisobutylaluminum hydride in toluene (55 mL, 0.055 mol) was added slowly drop-wise to the reaction mixture. The reaction mixture was warmed to −45° C. and stirred at this temperature for 35 minutes. At this time, TLC (10% ethyl acetate/hexanes) indicated nearly complete consumption of the starting material. The reaction mixture was quenched at −45° C. with ethyl acetate. Saturated aqueous sodium potassium tartrate was added, and the reaction mixture was warmed to room temperature and stirred at room temperature for 1 hour. The organic phase was separated, dried over Na2SO4, and concentrated to a yellow oil. A solution of this crude product and dichloromethane (200 mL) was evaporated onto silica gel, and the dry silica gel-supported product was loaded onto a 120 g silica gel column. Flash chromatography was carried out using an ISCO purification system (95:5 hexanes-ethyl acetate ramped to 4:1 hexanes-ethyl acetate). (2-Bromo-4-chloro-phenyl)-methanol was isolated as 5.57 g (60% yield) of a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:16][C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:26]=1)[C:20]([O:22]C)=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>C1COCC1>[CH2:28]([O:27][C:25]1[CH:24]=[C:19]([CH:18]=[C:17]([O:16][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:10][CH2:11][CH3:12])[CH:26]=1)[CH2:20][OH:22])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCOc1cc(OCCCCCCCCC)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCCCC)c1
Reaction time: 0.5 h

Procedure:
To a flame dried 1 L RBF containing a stir bar, LAH (1.80 g, 47.5 mmol) was added. The RBF was placed in an ice bath and the reaction was capped with a septum containing a nitrogen gas line and an out-vent. Dry THF (10 mL) was added through the septum while the mixture was stirring. Methyl 3,5-dinonyloxybenzoate (20 g, 39.6 mmol) was dissolved and added in 60 mL dry THF, drop-wise through the septum. After 30 minutes, the nitrogen line and out-vent were removed and the septum was changed. The mixture was allowed to stir overnight. The RBF was placed in an ice bath. Distilled water (250 mL) was added drop-wise through the septum until the color of the reaction mixture turned white-grey. The reaction mixture was allowed to stir at room temperature for 10 minutes and then 100 mL 1M hydrochloric acid was added until the pH reached lower than 2. The mixture was then extracted with ether (5 times using 200 mL). The ether layers were combined and then washed with 200 mL distilled water, 200 mL of aqueous sodium carbonate (5%), 200 mL distilled water, and 200 mL brine, and then dried with magnesium sulfate and gravity filtered. The solvent was removed under reduced pressure yielding 13.2 g or 92.6%. The NMR characterization data for the derivative is as follows. 1NMR (300 MHz, CDCl3): 0.87 (t, J=6.6, 6H, CH2CH3), 1.15-1.6 (m, 36H, CH2(CH2)9), 1.76 (p, J=8.0, 4H, OCH2CH2), 3.9 (t, J=6.6, 4H, OCH2CH2), 4.6 (d, J=5.0, 2H, ArCH2), 6.36 (t, J=2.2, 1H, ArH), 6.52 (d, J=2.2, 2H, ArH).