Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2[CH2:4][CH:3]1C(OC)=O.CS(C)=O.[Na+].[Cl-]>O>[O:1]=[C:2]1[CH:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2[CH2:4][CH2:3]1
Reactant: COC(=O)C1CN2CCN(C(=O)OC(C)(C)C)CC2C1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN2CCC(=O)C2C1
Temperature: 130 °C

Procedure:
A mixture of 2-tert-butyl 7-methyl 8-oxohexahydropyrrolo[1,2-a]pyrazine-2,7(1H)-dicarboxylate (Example 35B, 131 g, 0.44 mol), dimethyl sulfoxide (530 mL), NaCl (25.6 g, 0.44 mol) and water (32 g, 1.75 mol) was heated to 130° C. and maintained at that temperature for 2 hours. The reaction mixture was cooled, diluted with water (1 L) and extracted with ethyl acetate (1 L×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel eluting with 30-40% ethyl acetate in petroleum ether to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 2.23-2.42 (m, 3H), 2.47-2.60 (m, 1H), 2.60-2.78 (m, 1H), 2.82-2.98 (m, 1H), 3.02-3.10 (m, 1H), 3.32-3.40 (m, 1H), 3.65-3.85 (m, 1H), 3.99-4.20 (bs, 1H), 4.20-4.45 (bs, 1H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([C:16]3[N:20]4[CH:21]=[C:22]([S:25][C:26]5[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=5)[CH:23]=[CH:24][C:19]4=[N:18][N:17]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:36][C:37]([NH:39][C:40]1[N:44]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:43]=[C:42]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:41]=1)=O.CCN(C(C)C)C(C)C>CS(C)=O>[C:52]([C:42]1[CH:41]=[C:40]([NH:39][C:37]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([S:25][C:22]3[CH:23]=[CH:24][C:19]4[N:20]([C:16]([C:12]5[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][N:1]6[CH2:2][CH2:3][O:4][CH2:5][CH2:6]6)[CH:11]=5)=[N:17][N:18]=4)[CH:21]=3)=[CH:31][CH:30]=2)=[O:36])[N:44]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:43]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Nc1ccc(Sc2ccc3nnc(-c4cccc(OCCN5CCOCC5)c4)n3c2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Sc3ccc4nnc(-c5cccc(OCCN6CCOCC6)c5)n4c3)cc2)cc1
Yield: 40.9 %

Procedure:
A mixture of Example 10 step c (315 mg, 0.703 mmol), 5-(2,2,2-trichloroethoxycarbonyl)amino-3-tert-butyl-1-p-tolyl-1H-pyrazole (299 mg, 0.703 mmol) and DIPEA (116 μL, 0.675 mmol) in DMSO (3 mL) was heated at 55° C. for 24 h. The reaction was concentrated in vacuo and the residue purified by reverse phase preparative HPLC (Method 3) to afford the title compound (202 mg, 41%) as an off-white solid. LCMS (Method 4): Rt 8.46 min, m/z 703 [MH+]. 1H NMR (400 MHz, CDCl3): δ 9.30 (1 H, br s), 8.34 (1 H, br s), 8.16 (1 H, s), 7.49-7.41 (3 H, m), 7.37 (1 H, d, J 9.6), 7.29 (2 H, d, J 8.4), 7.25-7.20 (2 H, m), 7.18 (2 H, d, J 8), 7.09-7.04 (2 H, m), 6.90 (2 H, d, J 8), 6.44 (1 H, s), 4.15 (2 H, t, J 5.4), 3.72 (4 H, t, J 4.5), 2.88 (2 H, t, J 5.4), 2.64 (4 H, t, J 4.4), 2.11 (3 H, s), 1.30 (9 H, s).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Cl:5][CH2:6][S:7](Br)(=[O:9])=[O:8]>ClCCl>[CH:1]([NH:4][S:7]([CH2:6][Cl:5])(=[O:9])=[O:8])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Br)CCl
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 11.8 g (0.2 mol) sample of isopropylamine was added dropwise to a cooled (-60° C.) solution of 19.3 g (0.1 mol) chloromethanesulfonyl bromide in 200 ml dichloromethane. The reaction was then allowed to warm to about 25° C. and stirred about 16 hours. The reaction mixture was then filtered, washed with water, dried over magnesium sulfate and evaporated to give crude N-isopropyl chloromethanesulfonamide.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[C:10]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[C:3]=1[CH3:9])(=[O:12])[CH3:11]
Reactant: Cc1c(N)cccc1I
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(I)c1C
Temperature: 0 °C

Procedure:
Charge a 5 L, 3 neck flask equipped with a mantle, stirrer, condenser, with 708 grams (5M) 3-Iodo-2-Methyl Aniline, followed by 700 ml glacial acetic acid. Add in a stream of 520 grams (5.1M) acetic anhydride and allow the solution to come to a gentle reflux for an hour. The solution is allowed to cool and poured in a stream in a large container of 8 L ice water. The product will crystallize immediately and is filtered and squeezed under vacuum and air-dried. Yield was 900 grams (Theoretical yield=918 g).
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].C1(O)C=CC=CC=1.Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[CH:6]([C:5]1[CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]([O:1][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:3]([O:13][CH3:14])[CH:4]=1)=[O:7]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: COC(=O)CBr
Solvent: Oc1ccccc1
Product: COC(=O)COc1c(OC)cc(C=O)cc1[N+](=O)[O-]

Procedure:
Using 4-hydroxy-3-methoxy-5-nitrobenzaldehyde as the phenol and methyl 2-bromoacetate as the alkylating agent in the general procedure for alkylation of substituted 2-nitrophenols gives the title compound as a dark orange oil: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.66 (s, 3H) 3.97 (s, 3 H) 4.98 (s, 2H) 7.83 (d, J=1.77 Hz, 1H) 8.05 (d, J=1.77 Hz, 1H) 9.97 (s, 1H). ESI-MS: m/z 270.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][C:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[C:27]([CH3:38])[N:26]([C@H:39]2[CH2:44][CH2:43][C@H:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:41][CH2:40]2)[N:25]=1.[F-].[K+].O>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.O1CCOCC1>[Cl:22][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:24]([CH3:23])=[N:25][N:26]([C@H:39]4[CH2:40][CH2:41][C@H:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:43][CH2:44]4)[C:27]=3[CH3:38])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Reactant: CCOC(=O)[C@H]1CC[C@H](n2nc(C)c(B3OC(C)(C)C(C)(C)O3)c2C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CC[C@H](n2nc(C)c(-c3cnc4[nH]cc([C@H](C)c5c(OC)ccc(F)c5Cl)c4c3)c2C)CC1

Procedure:
A mixture of 5-bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (57.8 mg, 0.150 mmol), ethyl trans-4-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanecarboxylate (62.3 mg, 0.166 mmol), Pd(PPh3)4 (8.70 mg, 0.00753 mmol), potassium fluoride (26.2 mg, 0.452 mmol) and 4:1 dioxane:H2O (3 mL, 30 mmol) was heated to 90° C. for 2 h. The organic solvent was removed in vacuo, and the material was extracted with DCM and water. The organic layer was purified via column chromatography, eluting with 1-3% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=553.24/555.24 (100/50) [MH+]. HPLC: tR=1.71 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]=[C:3]1[SH:9].[CH3:10][C:11](C)([O-])C.[K+].C(I)C>O1CCCC1>[CH2:10]([S:9][C:3]1[N:2]([CH3:1])[C:6]([CH2:7][OH:8])=[CH:5][N:4]=1)[CH3:11]
Reactant: Cn1c(CO)cnc1S
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCSc1ncc(CO)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
4.33 g of (1-methyl-2-mercaptoimidazol-5-yl)methanol was added to 90 ml of tetrahydrofuran. Thereto 3.70 g of potassium t-butoxide and 5.15 g of ethyl iodide were then added under ice-cooling. The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 4.82 g of (2-ethylthio-1-methylimidazol-5-yl)methanol.
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)([CH3:4])=[O:3].[I:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28](Cl)=[O:29].C(N(C(C)C)CC)(C)C.[I-]>ClCCl>[CH3:4][P:2]([CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][C:16]([NH:17][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:33]([CH3:34])=[C:25]([I:24])[CH:26]=3)=[CH:15][CH:14]=2)[CH2:10][CH2:11]1)([CH3:1])=[O:3]
Reactant: CP(C)(=O)CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1I
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CP(C)(C)=O)CC3)c(C(F)(F)F)c2)cc1I
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-({4-[(dimethylphosphoryl)methyl]piperazin-1-yl}methyl)-5-(trifluoromethyl)aniline (yellow solid, 3.66 mmole, 1.0 eq.) was dissolved in 15 mL anhydrous dichloromethane. 3-iodo-4-methylbenzoyl chloride (1.58 grams, 5.64 mmole, 1.54 eq.) was added in one portion. At 0° C., under N2 protection, diisopropylethyl amine (2.4 mL, 14.0 mmole, 3.8 eq.) was added dropwise in 3 minutes. The reaction mixture was stirred at 0° C. under N2 for 30 minutes. It was then evaporated to remove most of the volatile components. The residue was purified via column chromatography (elution sequence: 100% dichloromethane-1% MeOH/dichloromethane/sat.NH3-10% MeOH/dichloromethane/sat.NH3). 40 mg of light yellow color oil was obtained and identified as the desire iodide. MS (LC/MS): 592.3 [M−].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6]([CH:12]([C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19])[O:13][SiH:14]([CH3:16])[CH3:15])=[CH:5]2.[H-].[Na+].[C:25]([O:29][C:30]([N:32]1[CH2:36][C@H:35]([CH3:37])OS1(=O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:36][C@H:35]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[C:10]([CH3:11])[CH:9]=2)[CH:5]=[C:6]1[CH:12]([C:17]([CH3:21])([CH3:22])[CH:18]([CH3:19])[CH3:20])[O:13][SiH:14]([CH3:15])[CH3:16])[CH3:37])([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: Cc1cc2[nH]c(C(O[SiH](C)C)C(C)(C)C(C)C)cc2cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1Br)cc(C(O[SiH](C)C)C(C)(C)C(C)C)n2[C@H](C)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.95 g 5-bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-methyl-1H-indole in 10 mL N,N-dimethylformamide was added 0.143 g sodium hydride (55-65%, mineral oil) and the mixture was stirred 30 min at room temperature. To the resulting mixture was added (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (0.703 g) and the mixture was stirred 2 h at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with 10% citric acid and brine, dried over magnesium sulfate and purified by chromatography on silica gel with 5:1 hexane:ethyl acetateto yield 0.789 g of the title compound as a slightly yellow oil. MS: M+H=541.3.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.Cl.[CH3:20]O>>[CH3:20][O:15][C:14]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][CH2:6][C:5]2[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1)=[O:16]
Reactant: CO
Reactant: O=C(O)c1ccc(NCc2ccc(F)cc2)cn1
Agent: Cl
Product: COC(=O)c1ccc(NCc2ccc(F)cc2)cn1

Procedure:
50 g of 5-(p-fluorobenzylamino)-pyridine-2-carboxylic acid are suspended in 700 ml of methanol and the solution saturated with gaseous hydrogen chloride. The saturated solution is refluxed for 31/2 hours and most of the methanol is removed under reduced pressure. The concentrate is poured into ice water and the mixture neutralized with sodium bicarbonate. It is extracted with ethyl acetate-diethyl ether (1:1), the organic phase washed with water, dried and evaporated. The residue is crystallized from ethyl acetate-diethyl ether (1:5), to yield the 5-(p-fluorobenzylamino)-pyridine-2-carboxylic acid methyl ester melting at 107°-108.5°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10]>ClCCl>[Br:8][C:7]1[C:2]([NH:1][C:15]([NH:14][C:12](=[O:13])[O:11][CH2:9][CH3:10])=[S:16])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1ncccc1Br
Solvent: ClCCl
Product: CCOC(=O)NC(=S)Nc1ncccc1Br
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 2-amino-3-bromopyridine (50.0 g, 289 mmol, 1 equiv) in dichloromethane (500 mL) was added dropwise ethoxycarbonyl isothiocyanate (39.0 g, 297 mmol, 1.03 equiv) at room temperature. After 2 h, dichloromethane was removed in vacuo to provide crude ethyl [(3-bromopyridin-2-yl) carbamothioyl]carbamate (88 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[OH:20][C:21]1[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:25][CH:26]=1>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:25]3[CH:26]=[C:21]([OH:20])[CH:22]=[CH:23][CH:24]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Oc1cccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 3-hydroxyphenylboronic acid pinacol ester with reaction time of 15 h. Chromatography (hexane/ethyl acetate 1:1) gave the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([N:21]2[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=[O:27])[CH2:22]2)[CH:3]=1.C1C(=O)N([Br:36])C(=O)C1>CC#N.CO>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([N:21]2[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=[O:27])[CH2:22]2)[C:3]=1[Br:36]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(N2CCC(C(=O)O)C2)nc2c(-c3cnc4ccccc4c3)cnn12
Solvent: CO
Solvent: CC#N
Product: Nc1c(Br)c(N2CCC(C(=O)O)C2)nc2c(-c3cnc4ccccc4c3)cnn12
Reaction time: 1 h

Procedure:
To a solution of 1-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine-3-carboxylic acid (17 mg, 0.033 mmol) in a 2:1 mixture of CH3CN/MeOH (1.0 mL) was added NBS (6.2 mg, 0.033 mmol). The mixture was stirred at it for 1 h then concentrated in vacuo. The residue was purified by prep-LC to afford the title compound. LC/MS RT=3.27 min. Mass calculated for, M+H 453.07, observed 453.07
Reaction SMILES: C([O:3][C:4]([C:6]1[N:19]([CH2:20][C:21]2[CH:25]=[C:24]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[O:23][N:22]=2)[C:9]2=[CH:10][N:11]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:13]=[C:8]2[CH:7]=1)=[O:5])C>C1COCC1.CO>[Cl:31][C:28]1[S:27][C:26]([C:24]2[O:23][N:22]=[C:21]([CH2:20][N:19]3[C:9]4=[CH:10][N:11]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:13]=[C:8]4[CH:7]=[C:6]3[C:4]([OH:5])=[O:3])[CH:25]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cc2cc(OCCOC)ncc2n1Cc1cc(-c2ccc(Cl)s2)on1
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1cc2cc(C(=O)O)n(Cc3cc(-c4ccc(Cl)s4)on3)c2cn1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 1.3 g (2.814 mmol) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester in 30 mL THF and 15 mL MeOH 11.26 mL 1M LiOH solution were added and the mixture was stirred at 50° C. for 3 h. The organic solvents were removed in vacuo, 50 mL of water were added and the pH was adjusted to pH 2 with 1N HCl solution. The desired product precipitated and was filtered, washed with water and dried over P2O5. Yield 1.11 g.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=2[F:26])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[ClH:1].[F:26][C:17]1[C:18]([F:25])=[C:19]([F:24])[C:20]([F:23])=[C:21]([F:22])[C:16]=1[O:15][CH:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: Fc1c(F)c(F)c(OC2CCN(Cc3ccccc3)CC2)c(F)c1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.1 %

Procedure:
To 2.0 g of 10% palladium on carbon was added 6.0 g of 1-benzyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine hydrochloride in 250 ml of methanol. The reaction mixture was pressurized to 50 psi with hydrogen and shaken on a Parr apparatus at room temperature for five hours. The mixture was then filtered and concentrated. Recrystallization of the concentrate from hot isopropanol afforded 1.9 g (42%) of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine hydrochloride, m.p. 187°-190° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:42](Cl)(=[O:47])[CH2:43][CH2:44][CH2:45][CH3:46].N>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([C:11]1([N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:23][CH:24]=2)[C:42](=[O:47])[CH2:43][CH2:44][CH2:45][CH3:46])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1-c1ccc(CNC2(C(=O)OCc3ccccc3)CCCCC2)cc1
Reactant: CCCCC(=O)Cl
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)C1(C(=O)OCc2ccccc2)CCCCC1
Reaction time: 1 h

Procedure:
A solution of 2.9 g (6.8 mmol) of N-(1-benzyloxycarbonylcyclohexyl)-N-(2'-cyanobiphenyl-4-ylmethyl)-amine and 4.4 ml (26 mmol) of Hunig base in 50 ml of ethyl acetate is treated with 1.1 g (9 mmol) of pentanoyl chloride, and the mixture is heated to reflux for 24 hours. After cooling, the reaction mixture is treated with 20 ml of aqueous ammonia solution (2N) and stirred for 1 hour. The organic phase is separated, washed in succession with 2 N-hydrochloric acid, saturated sodium hydrogencarbonate solution and brine, dried and evaporated. The N-(1-benzyloxycarbonylcyclohexyl)-N-(2'-cyanobiphenyl-4-ylmethyl)-N-pentanoyl-amine is thus obtained in the form of a brown oil [Rf : 0.44 (toluene/methanol=19:1)], which is used for further reactions in crude form.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:31][C@H:32]([OH:39])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[C:19]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:31][C@H:32]([OH:39])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[C:19]([CH2:27][CH:28]([CH3:29])[CH3:30])[CH:18]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Cc1cc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.6 %

Procedure:
To a solution of methyl 4′-[2-[[tert-butoxycarbonyl]-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-isobutyl-4-biphenylcarboxylate (390 mg) in methanol (3.90 ml) and tetrahydrofuran (1.56 ml) was added 1N aqueous sodium hydroxide solution (2.20 ml) and the mixture was stirred at room temperature for 2 days. Methanol and tetrahydrofuran were removed by evaporation under reduced pressure and to the mixture was added ethyl acetate (20 ml). The pH was adjusted to 4.3 with 1N hydrochloric acid and the organic layer was separated, washed with water (20 ml) and brine (20 ml) and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave a crude product which was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/2) to give 4′-[2-[[tert-butoxycarbonyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]-ethyl]-3-isobutyl-4-biphenylcarboxylic acid (291 mg) as a white solid (foam).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[NH:4][C:5]1[C:10]([NH2:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=1.[C:19](Cl)(Cl)=[O:20]>C1C=CC=CC=1>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[N:4]1[C:5]2=[N:6][CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=[C:10]2[NH:11][C:19]1=[O:20]
Reactant: O=C(Cl)Cl
Reactant: Nc1cc([N+](=O)[O-])cnc1Nc1ccccc1F
Solvent: c1ccccc1
Product: O=c1[nH]c2cc([N+](=O)[O-])cnc2n1-c1ccccc1F
Reaction time: 2 h

Procedure:
The product from Step B (750 mg.) is dissolved in 150 ml. of benzene and treated with phosgene until reaction is complete. After standing 2 hours, the precipitate is collected and recrystallized from ethanol to give 1,3-dihydro-3-(2-fluorophenyl)-6-nitroimidazo[4,5-b]pyridin-2-one, m.p. 234°-236° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:15]([O:14][C:12]([CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])=[O:13])[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-hydroxybenzaldehyde (5.17 g, 42.34 mmol), K2 CO3 (5.85 g) and acetone (50 ml) was added ethyl bromoacetate (5.2 ml). The reaction mixture was stirred at room temperature overnight, additional K2CO3 (1 equivalent) was added, the mixture was stirred for one hour, then additional ethyl bromoacetate (0.5 equivalents) was added and the mixture was stirred at room temperature until the reaction was complete. The reaction mixture was filtered, water was added to the filtrate and the solvent was removed. The residue was dissolved in ether, extracted with 1M NaOH (2×100 ml), and the ether layer was dried over MgSO4 and stripped to afford, as a liquid, 7.89 g of 3-(ethoxycarbonylmethoxy) benzaldehyde.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[N-:17]=[N+:18]=[N-:19].[Li+]>CS(C)=O>[N:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [Li+]
Solvent: CS(C)=O
Product: N#Cc1ccccc1-c1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A mixture of 1.97 g (725 mole) of 4-bromomethyl-2'-cyanobiphenyl (EP 253,310), 445 mg (9.1 mmole) of lithium azide and 5 ml of dry DMSO was stirred at room temperature under nitrogen for one hour and then partitioned between 100 ml of ether and 100 ml of H2O. The organic phase was washed with 3×100 ml of H2O, then dried (MgSO4), filtered, and concentrated in vacuo to give a residual oil which solidified on standing. This solid was triturated with petroleum ether, collected on a filter, washed with petroleum ether and dried overnight to yield 1.15 g (61%) of the title compound as white crystals, mp 69°-70° C.; mass spectrum (EI) m/e 234 (M+). TLC in 4:1 hexane-EtOAc showed only minor impurities and the material was of sufficient purity to use in the next step.