Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]([NH:22][C:23](=[O:29])[O:24]C(C)(C)C)[C@H:10](O)[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:5]([F:8])=[N:6][CH:7]=1.FC(F)(F)C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:10]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=3)[O:29][C:23](=[O:24])[NH:22]2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cc(Br)cnc1F)[C@H](O)c1ccc(C(F)(F)F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N[C@H](c2cc(Br)cnc2F)[C@@H](c2ccc(C(F)(F)F)cc2)O1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a 25 mL round bottom flask was added tert-butyl (1R,2R)-1-(5-bromo-2-fluoropyridin-3-yl)-2-hydroxy-2-(4-(trifluoromethyl)phenyl)ethylcarbamate (250 mg, 0.53 mmol) in dichloromethane (8 mL). To this solution was added trifluoroacetic acid (1.021 mL, 13.25 mmol) and the reaction was allowed to stir over night at room temperature. The reaction solvent was evaporated in vacuo and the crude oil was diluted with ethylacetate and washed with saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and the solvent was then evaporated in vacuo and the crude residue was diluted with dry tetrahydrofuran. The solution was cooled to 0° C. and carbonyldiimidazole (86 mg, 0.530 mmol) was added and the reaction was allowed to stir overnight. The reaction solvent was then evaporated in vacuo and the crude solid was purified by silica gel chromatography 15% EtOAc/85% Hexanes to 50% EtOAc/50% Hexanes affording (4R,5R)-4-(5-bromo-2-fluoropyridin-3-yl)-5-(4-(trifluoromethyl)phenyl)oxazolidin-2-one (84 mg, 0.207 mmol, 39.1% yield) and its regioisomer as an inseparable mixture. LC/Mass spec. (Analytical HPLC method 2): RT=2.44 min. Mass=406.91 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].S(Cl)([Cl:19])=O>>[N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([Cl:19])=[O:7])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Product: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 94 %

Procedure:
0.56 g (0.00238 mol) of 2-nitro-4-trifluoromethyl-benzoic acid was dissolved in 7 ml of thionyl chloride and boiled under reflux for 2 hrs. The reaction mixture was concentrated and the residue was taken up twice in toluene and evaporated to dryness each time. 0.53 g (94%) of 2-nitro-4-trifluoromethyl-benzoyl chloride was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH3:13][CH:14]1[CH2:18][CH2:17][CH2:16][NH:15]1>CN(C=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[CH3:13])=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CC1CCCN1
Solvent: CN(C)C=O
Solvent: CO
Product: CC1CCCN1c1nncc2cc(Br)ccc12
Temperature: 120 °C

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (500 mg, 2.0 mmol) and 2-methylpyrrolidine (524 μl, 5.1 mmol) in DMF (3 mL) was heated at 120° C. in an oil bath for 8 h. The mixture was diluted with MeOH and concentrated over silica gel. The residue was purified using column chromatography (0-40% EtOAc in hexanes) to give the title compound as a brown amorphous solid. MS (ESI, pos. ion) m/z: 292.0, 294.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:40]([CH3:42])[CH3:41])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O:17][CH2:18][C:19](=[O:39])[C:20]1[CH:21]=[CH:22][C:23]2[C:32]3[CH:31]=[C:30]4[CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:29]4=[CH:28][C:27]=3[O:26][CH2:25][C:24]=2[CH:38]=1)=[O:16])=[O:8])=[O:4].[Br-:43].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CO.Cl>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:40]([CH3:42])[CH3:41])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O:17][CH2:18][C:19]([C:20]1[CH:21]=[CH:22][C:23]2[C:32]3[CH:31]=[C:30]4[CH2:33][CH2:34][CH:35]([Br:43])[C:36](=[O:37])[C:29]4=[CH:28][C:27]=3[O:26][CH2:25][C:24]=2[CH:38]=1)=[O:39])=[O:16])=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O)C(C)C
Reactant: [Br-]
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S,5S)-2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate (400 mg, 0.61 mmol) was dissolved in a solution of DCM (15 mL) and MeOH (6 mL), then treated with pyridinium tribromide (409 mg, 1.28 mmol). At 2 h, an additional portion of pyridinium tribromide (40 mg) was added. After stirring at RT for another 20 min, the reaction mixture was diluted with DCM and 10% HCl, and extracted with DCM. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure and the crude material was carried on without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.N(C(OCC)=O)=NC(OCC)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:17]2[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 72.7 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (3.62 g), 2-methyl-4-nitrophenol (2.55 g) and triphenylphosphine (5.25 g) in dichloromethane (100 ml), diethyl azodicarboxylate (3.2 ml) was added dropwise with stirring under ice-cooling, and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using dichloromethane as the eluent to afford the title compound (4.07 g) containing impurities as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](OC)(=[O:29])[CH2:25][C:26]([CH3:28])=[O:27].[H-].[Na+].C([Li])CCC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]2([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[O:18][C:24](=[O:29])[CH:25]=[C:26]([OH:27])[CH2:28]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCc1cccc(OCc2ccccc2)c1)C1CCCC1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(CCc2cccc(OCc3ccccc3)c2)(C2CCCC2)O1

Procedure:
The title compound was prepared as described in General Method 6 using 3-(3-benzyloxy-phenyl)-1-cyclopentyl-propan-1-one (3.3 g, 11.3 mmol) from Example YYYY, 2.45 mL (22.7 mmcl) of methyl acetoacetate, 0.93 g (23.2 mmol) of 60% NaH dispersion in mineral oil, 14.5 mL (1.6M, 23.2 mmol) of n-butyllithium and 40 mL of THF. The reaction mixture was quenched with 5 mL HOAc and the mixture was worked up in the normal manner.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]=O.[C:6]([O:10][C:11]([N:13]1[CH:22]([CH2:23][NH:24][CH:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)C>C(#N)C>[C:6]([O:10][C:11]([N:13]1[CH:22]([CH2:23][N:24]([CH:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:4][CH2:3][O:2][CH3:1])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: COC(=O)C(Cc1ccc(Cl)cc1)NCC1Cc2ccccc2CN1C(=O)OC(C)(C)C
Reactant: COCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CC#N
Product: COCCN(CC1Cc2ccccc2CN1C(=O)OC(C)(C)C)C(Cc1ccc(Cl)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of methoxyacetaldehyde (0.15 gm, 2.03 mmol), 3-{[2-(4-Chloro-phenyl)-1-methoxycarbonyl-ethylamino]-methyl}-3,4dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester from preparation 3BC Step C (0.31 gm, 0.68 mmol) in acetonitrile was added sodium triacetoxyborohydride (0.72 gm, 3.38 mmol). After stirring overnight under a nitrogen atmosphere at r.t., additional acetaldehyde (0.25 gm) dissolved in acetonitrile and sodium triacetoxyborohydride (0.21 gm) was added, and the mixture was stirred for about 8.5 hours. The mixture was quenched at r.t. with 5N NaOH (5 mL). The aqueous phase was separated from the organic and extracted with ethyl acetate (4×). The combined organics were washed with a brine solution, and then dried, filtered and concentrated. Chromatography (gradient of ethyl acetate in hexane, 0 to 12%) gives about 0.23 g of 3-{[[2-(4-Chloro-phenyl)-1-methoxycarbonyl-ethyl]-(2-methoxy-ethyl)-amino]-methyl}-3,4dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester as a yellow oil (70%). MS (m/z, ES+): 517.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][C:30]#[N:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[C:29](=[CH:15]/[C:14]2[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:12][CH:13]=2)/[C:30]#[N:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(OCCCCCCCCO)cc1
Product: COc1ccc(/C(C#N)=C/c2ccc(OCCCCCCCCO)cc2)cc1OC
Yield: 46 %

Procedure:
(2Z)-2-(3,4-dimethoxyphenyl)-3-{4-[(8-hydroxyoctyl)oxy]phenyl}prop-2-enenitrile is prepared starting from 4-[(8-hydroxyoctyl)oxy]benzaldehyde and the commercial (3,4-dimethoxyphenyl)acetonitrile according the same procedure following for example 1 in 46% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:37])[CH2:11][CH:12]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH2:35][CH3:36])[CH:27]=1)[N:13]1[C:17](=[O:18])[C:16]2=[C:19]([CH3:24])[C:20]([CH3:23])=[CH:21][CH:22]=[C:15]2[C:14]1=[O:25])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[OH-].[OH-].[Pd+2]>[CH2:35]([O:34][C:28]1[CH:27]=[C:26]([CH:12]([N:13]2[C:17](=[O:18])[C:16]3=[C:19]([CH3:24])[C:20]([CH3:23])=[CH:21][CH:22]=[C:15]3[C:14]2=[O:25])[CH2:11][C:10]([NH:9][OH:8])=[O:37])[CH:31]=[CH:30][C:29]=1[O:32][CH3:33])[CH3:36]
Reactant: [H][H]
Reactant: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3ccc(C)c(C)c3C2=O)ccc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccc(C)c(C)c3C2=O)ccc1OC
Yield: 83.4 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3,4-dimethylphthalimido)propionamide was prepared by the procedure of Example 16 N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3,4-dimethylphthalimido)propanamide (0.63 g, 1.25 mmol), Pd(OH)2/C (100 mg) and hydrogen (50 psi) in ethyl acetate and methanol (30 mL each) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3,4-dimethylphthalimido)propionamide as a white solid (430 mg, 84% yield): mp, 197.0-202.5° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=7.2 Hz, 3H, CH3), 2.35 (s, 3H, CH3), 2.56 (s, 3H, CH3), 3.09 (d, J=7.09 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 3.97 (q, J=6.9 Hz, 2H, CH2), 5.65 (t, J=7.9 Hz, 1H, NCH), 6.89 (br s, 2H, Ar), 7.00 (br s, 1H, Ar), 7.59 (br s, 2H, Ar), 8.78 (br s, 1H, OH), 10.56 (br s, 1H, NH); 13C NMR (DMSO-d6) δ13.22, 14.65, 19.33, 34.21, 49.88, 55.43, 63.72, 111.75, 112.40, 119.62, 120.39, 127.76, 129.33, 131.36, 134.71, 136.50, 145.13, 147.62, 148.48, 166.02, 167.32, 168.65; Anal Calcd for C22H24N2O6+0.3 H2O: C, 63.24; H, 5.93; N 6.70. Found: C, 63.11;H, 5.88; N, 6.67.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:22][CH2:23][O:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)(=O)=O.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:22][CH2:23][O:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CCCC2)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccc(OCCOC3CCCC3)cc2)cc1

Procedure:
A solution of 24 g (0.12 mol) of 4-benzyloxyphenol in 100 cc of DMF is added dropwise to a 50% suspension of 6.2 g (0.132 mol) of NaH in 50 cc of DMF. When the evolution of gas has ended, a solution of 36 g (0.127 mol) of 2-cyclopentyloxyethyl tosylate in 100 cc of DMF is then added. The mixture is stirred for half an hour. It is then heated for 2 hours at 55°-60° C. with stirring. The reaction mixture is poured into iced water. Extraction is carried out with diethyl ether. The ether phase is washed with dilute sodium hydroxide solution and then with water, dried and evaporated to dryness.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.CCCCCCC>C(Cl)Cl>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:7][CH:8]=1
Reactant: OCCCc1ccc(C(F)(F)F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=CCCc1ccc(C(F)(F)F)cc1
Reaction time: 4 h
Yield: 84.1 %

Procedure:
In an inert atmosphere, 3-(4-trifluoromethyl-phenyl)-propan-1-ol (1.02 g, 5 mmol) was dissolved in DCM (10 ml) and slowly added to a suspension of PCC (1.61 g, 7.5 mmol) in anhydrous DCM (15 ml). Stirring was continued for 4 h at rt. Anhydrous heptane (10 ml) was added to the reaction mixture followed by filtration over a pad of silicagel (15 g). The filtrate was evaporated to give 850 mg of 3-(4-trifluoromethyl-phenyl)-propionaldehyde. LC-MS: tR=0.94 min; [M+H]+=no ionisation.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[N:23]2[N:27]=[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]3=[N:24]2)=[CH:7][CH:6]=1.[CH3:33][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>C1COCC1>[N:27]1[N:23]([C:17]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH2:13][CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([CH:4]([CH3:33])[C:3]([OH:2])=[O:32])=[CH:10][CH:9]=2)[N:24]=[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)Cc1ccc(OCCCOc2ccc(Cl)cc2-n2nc3ccccc3n2)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C(=O)O)c1ccc(OCCCOc2ccc(Cl)cc2-n2nc3ccccc3n2)cc1
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a solution of Compound 490 (0.45 g, 1 mmol) in THF (15 mL) was added KHMDS (3 mL, 1.5 mmol) at −78° C. under N2. The mixture was stirred at −78° for 0.5 hr and MeI (0.56g, 4 mmol) was added. The mixture was stirred at −78° for 2 hrs and was quenched with saturated aqueous NH4Cl, diluted with EtOAc organic layer was dried over NaSO4, evaporated and the residue was purified by flash chromatography on silica gel to afford 0.36g desired product.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=CC=[C:12]([C:13]3[CH:18]=CC=CC=3OC)[N:6]2[N:5]=1)=O.CS([C:24]1[N:29]=[CH:28][C:27]2=[CH:30][CH:31]=[C:32]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[N:26]2[N:25]=1)=O>>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:32]2[N:26]3[C:27]([CH:28]=[N:29][C:24]([N:5]4[C:18]5[CH:13]=[CH:12][N:6]=[CH:7][C:8]=5[N:9]=[CH:4]4)=[N:25]3)=[CH:30][CH:31]=2)[CH:34]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Product: c1cncc(-c2ccc3cnc(-n4cnc5cnccc54)nn23)c1

Procedure:
The compound was made in an analogous fashion to Example 322 replacing 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine with 2-Methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine to afford 60.57 mg of 1-(7-Pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-1H-imidazo[4,5-c]pyridine as a lyophilized powder. (M+H)=314.6. 1H NMR (400 MHz, DMSO, d6) δ 9.43 (s, 1H), 9.36 (s, 1H), 9.29 (s, 1H), 8.69 (m, 2H), 8.50 (m, 2H), 8.23 (m, 1H), 7.65 (m, 2H), 7.38 (d, 1H, J=4.84 Hz).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C@@H:43]([CH2:51][CH3:52])[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:45])(=O)=O.O>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[O:30][C@H:43]([CH2:51][CH3:52])[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:45])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: CCCCOC(=O)[C@H](CC)OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(OCCCN(Cc2cccc(O)c2)c2nc3ccccc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCOC(=O)[C@@H](CC)Oc1cccc(CN(CCCOc2ccc(OC)cc2)c2nc3ccccc3o2)c1
Reaction time: 0.17 h
Yield: 104.4 %

Procedure:
To a solution of N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)-3-hydrox ybenzylamine (530 mg) in acetonitrile (10 mL), potassium carbonate (272 mg) in a powder form was added at room temperature, and the resulting mixture was stirred for 10 minutes. The solution of n-butyl (S)-2-trifluoromethanesulfonyloxybutyrate (587 mg) in acetonitrile (10 mL) prepared in Preparative Example 6 was added to the reaction solution, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution, the mixture was extracted with toluene, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain a colorless oil (748 mg, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=1N)([O-])=O.Cl.N([O-])=O.[Na+]>O>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[C:4]3[C:5](=[CH:7][CH:8]=[C:9]([OH:11])[CH:10]=3)[NH:1][C:4]=2[CH:10]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)[nH]c1ccc(O)cc12
Temperature: 70 °C
Reaction time: 1.25 h
Yield: 25.4 %

Procedure:
2-Nitro-4-methoxyaniline (16.8 g) was added to water (30 mL) and concentrated hydrochloric acid (160 mL). The mixture was stirred at room temperature for 20 minutes and further at 70° C. for 75 minutes. An aqueous solution (30 mL) containing sodium nitrite (11.5 g) was added dropwise to the reaction solution while the reaction solution was maintained at a temperature of 5° C. or less by ice cooling. After the adding was completed, the reaction solution was stirred for 1 hour while maintained at 10° C. The reaction solution was filtered and the residue was washed with water (50 mL). The filtrate was cooled with ice, to which a mixed aqueous solution (120 mL) of sodium hydrogencarbonate (123 g) and 1,4-benzoquinone (12.3 g) was added dropwise over 1 hour. After the adding was completed, the reaction solution was stirred for 4 hours with ice cooling and then filtered. The thus obtained crystal was washed with water, dried, and then dissolved in methanol (200 mL) and acetic acid (20 mL). 10% Palladium/carbon (1.0 g) was added to the mixture, which was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction solution was filtered and the residue was washed with methanol (30 mL). Concentrated aqueous ammonia (50 mL) was added dropwise to the filtrate with ice cooling over 5 minutes. After the adding was completed, the reaction solution was allowed to warm to room temperature and stirred for 12 hours. The reaction solution was filtered and the crystal was washed with water and then dried under reduced pressure. The thus obtained crude product was purified by silica gel column chromatography (eluent: 3:1 to 0:1 hexane/ethyl acetate) to give the title compound (2.71 g).
Reaction SMILES: COC(C1C=C(C2C=CC(F)=CC=2)SC=1C(=O)[NH:18][CH2:19][C:20]([O:22]CC)=[O:21])=O.CO[C:28]([C:30]1[S:31][C:32]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[CH:33][C:34]=1[C:35](=O)[NH:36][CH2:37][C:38]([O:40]CC)=O)=[O:29]>>[F:50][C:47]1[CH:46]=[CH:45][C:44]([C:32]2[S:31][C:30]3[C:28]([OH:29])=[C:37]([C:38]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:40])[N:36]=[CH:35][C:34]=3[CH:33]=2)=[CH:49][CH:48]=1
Reactant: CCOC(=O)CNC(=O)c1cc(-c2ccc(F)cc2)sc1C(=O)OC
Reactant: CCOC(=O)CNC(=O)c1sc(-c2ccc(F)cc2)cc1C(=O)OC
Product: O=C(O)CNC(=O)c1ncc2cc(-c3ccc(F)cc3)sc2c1O

Procedure:
The title compound was prepared from 2-(ethoxycarbonylmethyl-carbamoyl)-5-(4-fluoro-phenyl)-thiophene-3-carboxylic acid methyl ester and 3-(ethoxycarbonylmethyl-carbamoyl)-5-(4-fluoro-phenyl)-thiophene-2-carboxylic acid methyl ester, example 34-a, under conditions analogous to experimental example 30-f. MS: (+) m/z 362.2 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17](=[O:33])[C:18]4[C:23]([F:24])=[CH:22][CH:21]=[C:20]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[C:19]=4[F:32])[CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>CO.[Pd]>[CH:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17](=[O:33])[C:18]4[C:23]([F:24])=[CH:22][CH:21]=[C:20]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[C:19]=4[F:32])[CH:14]=3)[NH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C4=CCCCC4)c3c2)c1F
Agent: [Pd]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C4CCCCC4)c3c2)c1F
Yield: 25 %

Procedure:
N-(3-cyclohexenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (40 mg, 0.084 mmol) was dissolved in methanol (1 mL), and 10% Pd/C (40 mg, 1 eq.) was then added. This mixture was subjected to 45 psi of hydrogen for 16 hours and filtered through GF/F filter paper. The filtrate was then concentrated. The resulting solids were purified by preparative TLC (2×0.5 mm plates, 10% MeOH/DCM as the eluent) to give N-(3-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (10 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 10.82 (s, 1H), 9.79 (br s, 1H), 8.32-8.39 (m, 2H), 7.50-7.56 (m, 1H), 7.19-7.28 (m, 2H), 3.07-3.15 (m, 2H), 2.68-2.78 (m, 1H), 1.96-2.02 (m, 2H), 1.70-1.84 (m, 5H), 1.38-1.49 (m, 4H), 1.21-1.31 (m, 1H), 0.95-1.03 (m, 3H); m/z (APCI-neg) M−1=475.3, (APCI-pos) M+1=477.2.