Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:37])[C@@H:6]([NH:25][C:26](=[O:36])[C:27]1[C:32]([F:33])=[CH:31][C:30](Br)=[CH:29][C:28]=1[F:35])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[CH2:2][CH3:3].O.[CH3:39][N:40](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:4][C:5](=[O:37])[C@@H:6]([NH:25][C:26](=[O:36])[C:27]1[C:32]([F:33])=[CH:31][C:30]([C:39]#[N:40])=[CH:29][C:28]=1[F:35])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[CH2:2][CH3:3]
Reactant: CN(C)C=O
Reactant: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cc(C#N)cc1F
Temperature: 85 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To a suspension of (S)-2-(4-bromo-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid propyl ester (5.78 g, 10 mmol), zinc cyanide (940 mg, 8 mmol), and tetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol) in DMF (40 mL, distilled and degassed) at room temperature. The resulting solution was heated to 85° C. and stirred for 24 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was cooled to room temperature and it was poured into water (100 mL) to afford a cloudy suspension. Then, the organic compound was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine solution (100 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified using an ISCO (150 g) column chromatography to afford 5.2 g (99% yield) of (S)-2-(4-cyano-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid propyl ester as an amorphous white solid. ES-HRMS m/e calcd for C27H26F2N4O5(M+H)+ 525.1944, found 525.1942.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[N:6]=[CH:5][C:4]([C:3]([N:25]2[CH2:30][CH2:29][S:28][CH2:27][CH2:26]2)=[O:24])=[CH:9][CH:8]=1
Reactant: C1CSCCN1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Yield: 89 %

Procedure:
As described for example 272, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (97.6 mg, 0.3 mmol) was converted, using thiomorpholine instead of 4-aminotetrahydropyran, to the title compound (106 mg, 89%) which was obtained as a white solid. MS: m/e=397.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:19]([NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](OC)=[O:36].O>CN(C=O)C>[O:36]=[C:35]1[CH2:34][O:1][C:2]2[C:19](=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)[N:20]1[CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)c(NC3CCOCC3)cc2CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(C1CCOCC1)C(=O)CO3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 215 mg of t-butyl 7-hydroxy-8-(tetrahydro-2H-pyran-4-ylamino)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 4 ml of DMF were added 98 mg of potassium carbonate and 0.062 ml of methyl bromoacetate, followed by stirring at room temperature for 6 hours. To the reaction mixture was added water, followed by extraction with EtOAc twice. The combined organic layer was washed with saturated brine three times, dried over anhydrous sodium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. To a solution of 259 mg of the resulting residue in 7 ml of EtOH was added 1.2 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at 50° C. overnight. Further, 1.2 ml of a 1 M aqueous hydrochloric acid solution was added thereto under ice-cooling, followed by extraction with chloroform twice, and the combined organic layer was dried over anhydrous sodium sulfate and then filtered. The solvent was evaporated under reduced pressure. To a solution of 239 mg of the resulting residue in 4 ml of DMF were added 120 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 84 mg of HOBt at room temperature, followed by stirring at room temperature overnight. Water was added thereto, followed by extraction with EtOAc twice. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 153 mg of t-butyl 3-oxo-4-(tetrahydro-2H-pyran-4-yl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O.[CH:13]([NH2:16])([CH3:15])[CH3:14].CO>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:13]([NH:16][CH:7]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)([CH3:15])[CH3:14]
Reactant: CC(C)N
Reactant: COc1cccc2c1CCC2=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cccc2c1CCC2NC(C)C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxy-1-indanone (0.71 g) and iso-propylamine (8 ml) in dichloromethane (10 ml) was added 1M solution of titanium(IV) chloride in dichloromethane (11 ml) at -60° C. for 15 minutes. The reaction mixture was stirred for 3 hours at the same temperature. Methanol (15 ml) was added to the reaction mixture. After being stirred for 2 hours at room temperature, the solution was evaporated in vacuo. The residue was partitioned between ethyl acetate and 1N aqueous NaOH solution. The insoluble material was filtered off by zeolite. The organic layer was washed with brine. The dried solvent was evaporated in vacuo to give 1-isopropylamino-2,3-dihydro-4-methoxy-1H-indene (0.89 g). MS (m/z): 206 (M+ +1) NMR (CDCl3, δ): 7.18 (1H, dd, J=7.8, 7.8 Hz), 6.97 (1H, d, J=7.8 Hz), 6.71 (1H, d, J=7.8 Hz), 4.30 (1H, t, J=6.7 Hz), 3.83 (3H, s), 3.20-2.87 (2H, m), 2.80-2.60 (1H, m), 2.50-2.35 (1H, m), 2.00-1.68 (1H, m), 1.13 (3H, d, J=6.9 Hz), 1.12 (3H, d, J=6.9 Hz)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: O=C1CNCCN1
Product: O=C1CN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CCN1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-piperazinone according to conditions described in general procedure C. Mp: 140-142° C.; 1H NMR (400 MHz, CDCl3) δ 1.62-1.69 (m, 6 H), 3.25-3.28 (m, 6 H), 3.82 (s, 2 H), 4.14 (s, 2 H), 6.20 (d, J=5.5 Hz, 1 H), 6.38 (s, 1 H), 6.76 (d, J=11.7 Hz, 1 H), 7.00 (d, J=8.0 Hz, 1 H), 7.26 (d, J=8.0 Hz, 1 H), 7.32 (s, 1 H), 7.46-7.55 (m, 2 H), 7.83-7.92 (m, 3 H), 8.20-8.21 (m, 1 H), 8.36 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:46]([O:50][C:51](=[O:61])[NH:52][CH2:53][C@H:54]1[CH2:59][CH2:58][C@@H:57](O)[CH2:56][CH2:55]1)([CH3:49])([CH3:48])[CH3:47]>O1CCCC1.O>[C:46]([O:50][C:51](=[O:61])[NH:52][CH2:53][C@H:54]1[CH2:55][CH2:56][C@H:57]([O:12][C:7]2[C:6]3[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)[CH2:58][CH2:59]1)([CH3:49])([CH3:47])[CH3:48]
Reactant: Oc1ccnc2c(F)cccc12
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Oc2ccnc3c(F)cccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Fluoroquinolin-4-ol (948 mg, 5.81 mmol), triphenylphosphine (1.52 g, 5.81 mmol) and DIAD (1.17 g, 5.81 mmol) were dissolved in tetrahydrofuran (140 mL). After adding tert-butyl-N-[(cis-4-hydroxycyclohexyl)methyl]carbamate (1.11 g, 4.84 mmol), the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate and the combined organic phases were dried over sodium sulphate. After removal of the solvent residues and chromatographic purification of the residue, the product was obtained at 42% yield (960 mg).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[Cl:28][C:29]1[C:36]([N:37]([C:39](=[O:56])[CH2:40][NH:41][C:42](=[O:55])[CH:43]=[CH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51](=[O:54])[NH:52][CH3:53])=[CH:47][CH:46]=2)[CH3:38])=[CH:35][CH:34]=[C:33]([Cl:57])[C:30]=1[CH2:31]Br>O>[Cl:28][C:29]1[C:36]([N:37]([C:39](=[O:56])[CH2:40][NH:41][C:42](=[O:55])[CH:43]=[CH:44][C:45]2[CH:46]=[CH:47][C:48]([C:51](=[O:54])[NH:52][CH3:53])=[CH:49][CH:50]=2)[CH3:38])=[CH:35][CH:34]=[C:33]([Cl:57])[C:30]=1[CH2:31][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CBr)c2Cl)cc1
Reactant: Cc1cc(OCc2ccccn2)c2cccc(O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(OCc5ccccn5)cc(C)nc34)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To an ice-cooled mixture of sodium hydride (40% in oil, 9 mg) and anhydrous N,N-dimethylformamide (1 ml) was added 8-hydroxy-2-methyl-4-(2-pyridylmethoxy)quinoline (53 mg), and the mixture was stirred at the same temperature for 30 minutes. To this mixture was added 2,6-dichloro-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyl bromide (103 mg), and the mixture was stirred at ambient temperature for 2.5 hours. Water (2 ml) was slowly added to the reaction mixture under ice-water cooling and the precipitates were collected by vacuum filtration and washed with water and diethyl ether. The crude product was purified by a preparative thin layer chromatography (chloroform-methanol-ammonium hydroxide) followed by trituration with ethyl acetate to give 8-[2,6-dichloro-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (77 mg) as a pinkish powder.
Reaction SMILES: Br.Br[CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=O.[NH2:18][C:19]([NH2:21])=[S:20].C(N(CC)CC)C>C(#N)C>[C:12]1([C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1cccnc1)C(Br)c1ccccc1
Reactant: NC(N)=S
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1nc(-c2cccnc2)c(-c2ccccc2)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
To a mixture of 2-bromo-2-phenyl-1-(3-pyridyl)ethanone hydrobromide (2.00 g) and thiourea (432 mg) in acetonitrile (30 mL), was added triethylamine (0.80 mL) dropwise and the resulting mixture was stirred at 80° C. for 3 h. The solvent was removed under reduced pressure and an aqueous saturated solution of sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The organic phases were washed with water, dried and concentrated under reduced pressure to give the amorphous title compound (1.10 g, yield 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH:5]=[O:6].ClC1C=C(C=CC=1OCC)C=[O:19]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[C:5]([OH:19])=[O:6]
Reactant: CCOc1ccc(C=O)cc1Cl
Reactant: CCCOc1ccc(C=O)cc1Br
Product: CCCOc1ccc(C(=O)O)cc1Br
Yield: 86 %

Procedure:
When the product of Step A was substituted for 3-chloro-4-ethoxybenzaldehyde in Example 49, Step A, the identical process afforded the title compound in 86% yield. 1H-NMR (DMSO-d6) 0.98 (tr, 3H, J=7.32 Hz); 1.68-1.79 (m, 2H); 4.06 (tr, 2H, J=6.39 Hz); 7.14 (d, 1H, J=8.7 Hz); 7.87 (dd, 1H, J=2.07, 8.61 Hz); 8.01 (d, 1H, J=2.04 Hz); 11.2 (broad s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:20]1([C:23]([NH2:31])([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)[CH3:24])[CH2:22][CH2:21]1>>[CH:20]1([C:23]([NH:31][C:10]([C:7]2[CH:6]=[C:5]([O:13][C@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)[CH3:24])[CH2:22][CH2:21]1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Reactant: C[C@@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Product: Cc1nc(C(C)(NC(=O)c2cc(O[C@H](C)C(F)(F)F)c(C3CC3)cn2)C2CC2)no1

Procedure:
The mixture of epimers was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 73a) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and isolated (135 mg, 70%) as light yellow oil. The mixture of epimers was separated by preparative chiral HPLC (Chiralpak AD, isopropanol/heptane) and the title compound was the first epimer collected and isolated as colorless oil; MS (ESI, m/z): 425.5 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15].N#N>CN(C=O)C.C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:13])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: N#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h
Yield: 76.7 %

Procedure:
To a solution of 5.0 g (1.0 eq, 28.6 mmol) 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine in 30 mL DMF under N2 at rt was added 1.37 g (1.2 eq, 34.3 mmol) of a 60% oil dispersion of NaB. After stirring for 5 minutes, 8.64 g (1.4 eq, 40.0 mmol) of p-nitrobenzyl bromide was added. The dark brown mixture was stirred for 2 hours under a blanket of N2 at rt. The mixture was diluted with 1 L CH2Cl2 and washed with 500 mL H2O and 500 mL saturated aqueous NaCl. The organic phase was dried over MgSO4 and concentrated to a yellow oil. The oil was flash chromatographed with 50% ethyl acetate/hexane. The product containing fractions were combined and concentrated to a yellow oil which crystallized on standing, yielding 6.81 g (76.8%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[H-].[Na+].Br[CH2:16][CH:17]([CH3:19])[CH3:18]>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11])[CH:17]([CH3:19])[CH3:18]
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(OCC(C)C)c(C(C)=O)c1
Temperature: 80 °C

Procedure:
A mixture of 10 g (0.06 mol) of 2′-hydroxy-5′-methoxyacetophenone, 2.6 g (0.066 mol) of 60% sodium hydride and 150 ml of dimethylformamide is heated for one hour at 80° C. 7.2 ml (0.066 mol) of 1-bromo-2-methylpropane are added dropwise. The mixture is heated for ten hours at 80° C. and is then poured into ice-water and extracted with ether. The ether solution is washed with normal sodium hydroxide solution. The dried (Na2SO4) organic phase is evaporated under reduced pressure (8.2 g; 62%).
Reaction SMILES: C(OC[C:10]1[C:18]2[C:13](=[CH:14][N:15]=[C:16]([C:19]([NH:21][OH:22])=[O:20])[CH:17]=2)[N:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH:11]=1)C1C=CC=CC=1.FC1C=C(F)C=CC=1CN1C2=CN=C(C=O)C=C2C=C1[C:47]([O:49][CH2:50][CH3:51])=[O:48]>>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[CH2:23][N:12]1[C:13]2=[CH:14][N:15]=[C:16]([C:19](=[O:20])[NH:21][OH:22])[CH:17]=[C:18]2[CH:10]=[C:11]1[C:47]([O:49][CH2:50][CH3:51])=[O:48]
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: CCOC(=O)c1cc2cc(C=O)ncc2n1Cc1ccc(F)cc1F
Product: CCOC(=O)c1cc2cc(C(=O)NO)ncc2n1Cc1ccc(F)cc1F

Procedure:
Ethyl 1-(2,4-difluorobenzyl)-5-formyl-1H-pyrrolo[2,3-c]pyridine-2-carboxyl ate. The title compound can be prepared by alkylation of ethyl 5-formyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (prepared according to J.-F. Rousseau, R. H. Dodd, X. Doisy, P. Potier, Heterocycles 1989, 28, 1101-1113) and 2,4-difluorobenzyl bromide in a manner similar to step (a) in Example 1. (b) 1-(2,4-Difluorobenzyl)-(2-ethoxycarbonyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid. The title compound can be prepared by oxidation of ethyl 1-(2,4-difluoro-benzyl)-5-formyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate according to the procedure by R. H. Dodd, M. Le Hyaric, Synthesis 1993, 295-287. (c) Ethyl 1-(2,4-Difluorobenzyl)-5-hydroxycarbamoyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate. The title compound can be prepared from 1-(2,4-difluorobenzyl)-(2-ethoxycarbonyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid following in a manner similar to step (c ) in Example 1.
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:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=2)[C:30](O)=[O:31])[N:21]=1>>[F:34][CH:19]([F:18])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=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])[N:21]=1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cncc(-c2noc(C(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cncc(-c2noc(C(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 24 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 5-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (45 mg, yield 24%). 1H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J=2.1 Hz, 1H), 9.20 (d, J=2.1 Hz, 1H), 8.82-8.78 (m, 1H), 8.75-8.74 (t, J=2.1 Hz, 1H), 8.04-8.00 (m, 3H), 7.74-7.48 (m, 1H), 7.38-7.33 (t, J=8.9 Hz, 2H), 3.55-3.53 (d, J=6.1 Hz, 2H), 1.31 (s, 6H). MS (ESI) m/z: Calculated for C22H18F3N5O3: 457.14. found: 458.2 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:22]([CH3:23])=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=2[CH3:24])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:16]([CH3:24])=[CH:17][C:18]([CH2:19][OH:20])=[CH:21][C:22]=2[CH3:23])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C=O)cc2C)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(CO)cc2C)c1C
Temperature: 25 °C

Procedure:
A mixture of 4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzaldehyde and sodium borohydride in methanol was stirred at room temperature. After standard work-up procedure and purification, the title compound was obtained as a solid. 1H NMR(CDCl3) d 7.06(s, 2H), 6.08(s, 1H), 4.64(s, 2H), 3.74(d, 1H), 3.33(m, 1H), 2.14(s, 3H), 2.13(s, 3H), 2.11(s, 6H) ppm.
Reaction SMILES: [CH3:1][N:2]([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])[C@@H:3]([C:24]([OH:26])=[O:25])[CH2:4][NH:5][C:6](=[O:23])[CH2:7][CH:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH2:22])=[N:20][OH:21])=[CH:15][CH:14]=2)[CH2:9]1.[C:34](OC(=O)C)(=O)[CH3:35]>C(O)(=O)C>[CH3:1][N:2]([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])[C@@H:3]([C:24]([OH:26])=[O:25])[CH2:4][NH:5][C:6](=[O:23])[CH2:7][CH:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:22]=[C:34]([CH3:35])[O:21][N:20]=3)=[CH:17][CH:18]=2)[CH2:9]1
Reactant: CCCCOC(=O)N(C)[C@H](CNC(=O)CC1CC(c2ccc(C(N)=NO)cc2)=NO1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCCOC(=O)N(C)[C@H](CNC(=O)CC1CC(c2ccc(-c3noc(C)n3)cc2)=NO1)C(=O)O
Yield: 95.1 %

Procedure:
To a suspension of (R)-Methyl-3-[[[3-[4-[amino(hydroxyimino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl]acetyl]amino]-N-(butoxycarbonyl)-L-alanine (1.05 g) in acetic acid (7 mL) was added acetic anhydride (0.35 g) dropwise. After the completion of addition, the reaction mixture was refluxed for 3 h. The solvent was distilled under vacuum and the solid was dried to give (R)-methyl-N-(butoxycarbonyl)-3-[[[4,5-dihydro-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-5-isoxazolyl]acetyl]amino]-L-alanine (1.05 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][NH2:11])=[O:4].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:39]=[N:40][C:41]([O:46][CH3:47])=[C:42]([O:44][CH3:45])[CH:43]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:45][O:44][C:42]1[CH:43]=[C:38]([CH:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:28][CH:27]=2)[C:23]2[NH:22][C:21](=[O:20])[N:10]([C:9]3[CH:8]=[CH:7][S:6][C:5]=3[C:3]([OH:2])=[O:4])[N:11]=2)[CH:39]=[N:40][C:41]=1[O:46][CH3:47]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cnc(OC)c(OC)c1
Reactant: COC(=O)c1sccc1NN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)cnc1OC
Temperature: 90 °C
Reaction time: 12 h

Procedure:
After adding 38 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 0.030 ml of triethylamine to a solution of 100 mg of {2-(5,6-dimethoxypyridin-3-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 1 ml of DMF, the mixture was stirred at 90° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 1.5 ml of methanol and 0.1 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 3 hours. Next, 1.0 ml of a 5N aqueous sodium hydroxide solution was added and the mixture was stirred at room temperature for 2 hours. After then adding 0.3 ml of acetic acid, the reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product of 3-(3-{(5,6-dimethoxypyridin-3-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic acid.