Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:58])=[C:11]([N:18]([CH2:27][C:28]2[N:29]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:32]=2)[C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH:12]=[C:13]([O:15][CH2:16][CH3:17])[CH:14]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH2:16]([O:15][C:13]1[CH:14]=[C:9]([OH:8])[C:10]([F:58])=[C:11]([N:18]([CH2:27][C:28]2[N:29]([C:39]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:32]=2)[C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[CH:12]=1)[CH3:17]
Reactant: CCOc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(N(Cc2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C#N)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(O)c(F)c(N(Cc2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of Intermediate 113.2 (620 mg, 0.790 mmol) in 5 mL THF at rt, was added TBAF (1M, 0.79 mL, 0.790 mmol). The mixture was stirred at rt for 1 h, then was diluted with EtOAc. The organic phase was washed with sat. NH4Cl (2×), H2O (2×) and brine, dried (Na2SO) and concentrated. The crude product was purified by flash chromatography (0 to 50% EtOAc/hexanes, gradient) to afford 530 mg (100%) of Intermediate 113.3 as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CC(O)C.C(=O)=O.C([Li])CCC.[CH2:26]([O:33][CH2:34][CH:35]1[CH2:38][C:37](=[O:39])[CH2:36]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:26]([O:33][CH2:34][CH:35]1[CH2:38][C:37]([C:2]2[CH:13]=[CH:12][C:5]([CH2:6][N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=2)([OH:39])[CH2:36]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CC(COCc2ccccc2)C1
Reactant: Brc1ccc(CN2CCCC2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: OC1(c2ccc(CN3CCCC3)cc2)CC(COCc2ccccc2)C1
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a stirring solution of 1-(4-bromo-benzyl)-pyrrolidine (1.9 g, 7.9 mmol) in 13 mL of tetrahydrofuran at −78 C (iPrOH/dry ice) was added slowly down the side of the flask a solution of n-butyl lithium (3.2 mL, 7.9 mmol, 2.5 M in THF). After 30 minutes a precooled −78 C (iPrOH/CO2 ice) solution of 3-benzyloxymethyl-cyclobutanone (1.0 g, 5.3 mmol, in 1 mL of THF) was added via cannula down the side of the flask (wash 1 mL). The resulting solution was stirred at −78 C for 30 minutes, then quenched with a saturated solution of aqueous NH4OH and diluted with EtOAc. The layers were separated and the organic layer was dried over magnesium sulfate, filtered through a fritted funnel and then concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a Biotage column, eluting with a gradient of 2% MeOH/CH2Cl2 w/0.1% NH4OH through 30% MeOH/CH2Cl2 w/0.1% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to yield the title compound (1.3 g, 71% yield) as a colorless oil and a 3:1 mixture of cis:trans isomers.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=2)O1.[CH3:28][O:29][C:30](=[O:41])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[C:32]=1Br.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C(OCC)C.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>[CH3:28][O:29][C:30]([C:31]1[C:32]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:22])=[O:23])=[CH:13][CH:14]=2)=[C:33]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:35][CH:36]=1)=[O:41]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)c1cccc([N+](=O)[O-])c1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
Heat the mixture of propane-2-sulfonic acid {2-[4-{4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiophen-3-yl}-amide(662 mg, 1.65 mmol), 2-bromo-3-nitro-benzoic acid methyl ester (390 mg, 1.5 mmol), Na2CO3(2M, 2.2 mL, 4.5 mmol) and Pd(PPh3)4 (260 mg, 0.26 mmol) and 15 ml of 1,4 dioxane under N2 to 80° C. overnight. After cooling to room temperature, dilute with diethyl ether (200 mL). Wash with water, saturated aq. sodium chloride, and dry over MgSO4. Remove solvent and purify by flash chromatography (Silica gel-hexane/EtOAc) to provide 6-nitro-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-2-carboxylic acid methyl ester (250 mg). MS (m/e): 478.7(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([CH3:15])[CH:12]=[C:13]([C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[O:23])[CH:14]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cccc1C(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccncc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1cc(C(=O)c2ccncc2)cc1C(=O)c1ccc(Cl)cc1
Yield: 26.9 %

Procedure:
A solution of 17.5 g (0.08 mole) of (4-chlorophenyl)(1-methyl-1H-pyrrol-2-yl)methanone, 14.4 g (0.088 mole) of isonicotinoyl chloride and 26.6 g of aluminum chloride (0.2 mole) in 280 mL of DCE was heated under reflux for 16 h. After cooling, the mixture was partitioned between CH2Cl2 and dilute NaOH solution. The organic layer was dried and the solvent was evaporated in vacuo. The residue was triturated with ether. The resulting solid was recrystallized from 2-PrOH to give 7 g (27%) of the title compound, mp 174-175° C. ES-MS m/z=325 (M++H). 1H NMR (300 MHz, CDCl3) δ 4.1 (s, 3H); 7.1 (s, 1H); 7.3(dd, 2H); 7.42 (dd, 2H); 7.45 (s, 1H); 7.8 (dd, 2H); 8.8 (dd, 2H). Anal calc'd for: C18H13ClN2O2: C, 66.57; H, 4.03; N, 8.63. Found: C, 66.34; H, 3.94; N, 8.53.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15](=[O:28])[CH2:16][CH2:17][C:18]2[S:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[C:22]=2[CH3:23])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].O.O.[OH-].[Li+].Cl>C(O)C>[CH3:1][C:2]1[CH:14]=[C:13]([C:15](=[O:28])[CH2:16][CH2:17][C:18]2[S:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[C:22]=2[CH3:23])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(C(=O)CCc2sc3ccccc3c2C)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)CCc2sc3ccccc3c2C)ccc1OCC(=O)O
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of ethyl 2-methyl-4-[3-(3-methylbenzothiophen-2-yl)propionyl]phenoxyacetate in ethanol (2 mL)/water (1 mL) was added lithium hydroxide monohydrate (70 mg, 1.7 mmol). The mixture was heated under reflux for 1 hour, cooled at room temperature. After addition of ice, the resultant mixture was acidified with 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from ethyl acetate/hexane to give the titled compound as a pale yellow crystal (120 mg, 59%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH2:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][NH:25]1.C(N(CC)CC)C>O1CCCC1>[CH2:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][N:25]1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCc3ccccc3C2)nc1-c1ccc(C)cc1
Yield: 58.8 %

Procedure:
This compound was prepared according to the method C from methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.095 g; 0.285 mmol), 1,2,3,4-tetrahydroisoquinoline (0.108 mL; 0.856 mmol) and triethyl amine (0.200 mL; 1.43 mmol) in tetrahydrofuran (2 mL). Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.072 g (58%) of the titled compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>O1CCOCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C=Cc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: O=[N+]([O-])CCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
A solution of 13.5 g (72 mmol) of 2-(3-Chlorophenyl)-1-nitroethene, from Step 2, in 200 mL of dioxane was added dropwise to a stirred suspension of 6 g (157 mmol) of sodium borohydride in a mixture of 140 mL of dioxane and 60 mL of ethanol. The reaction mixture was stirred at ambient temperature for 2 h and then the excess borohydride was quenched with acid. The reaction mixture was concentrated in vacuo and the residue was partitioned between methylene chloride and water (4:1). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel eluted with 20% methylene chloride in hexane to afford 6.3 g (48% yield) of the title compound; MS DCI-NH3M/Z: 203 (M+NH4)+ ; 1H NMR (CDCl3) δ3.3 (2H, t, J=7.5 Hz), 4.6 (2H, t, J=7.5 Hz), 7.05-7.3 (4H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)=[CH:12][CH:11]=[CH:10][C:9]=2[C:29]1[CH:34]=[CH:33][C:32]([C:35]([O:37]C)=[O:36])=[CH:31][C:30]=1[CH3:39])=[O:5])C.[Cl:40][C:41]1[CH:46]=[C:45]([Cl:47])[C:44]([Cl:48])=[CH:43][C:42]=1[OH:49].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[NH:7][C:6]([C:4]([OH:5])=[O:3])=[C:14]3[CH2:15][CH2:16][CH2:17][O:49][C:42]2[CH:43]=[C:44]([Cl:48])[C:45]([Cl:47])=[CH:46][C:41]=2[Cl:40])=[C:30]([CH3:39])[CH:31]=1)([OH:37])=[O:36]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CCOC(=O)c1[nH]c2c(-c3ccc(C(=O)OC)cc3C)cccc2c1CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)O)ccc1-c1cccc2c(CCCOc3cc(Cl)c(Cl)cc3Cl)c(C(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 127C (60 mg) in DMF (1 mL) was added 2,4,5-trichlorophenol (43 mg) and Cs2CO3 (500 mg). The mixture was stirred at room temperature overnight, diluted with ethyl acetate (150 mL), and washed with water and brine. After drying over Na2SO4, the combined organic layers were concentrated, and the concentrate was saponified with LiOH as described in EXAMPLE 65B. 1H NMR (300 MHz, DMSO-d6) δ 12.92 (m, 1H), 10.88 (s, 1H), 7.89 (s, 1H), 7.82 (m, 2H), 7.38 (s, 1H), 7.32 (d, 1H), 7.10 (m, 2H), 4.13 (t, 2H), 3.25 (t, 2H), 2.13 (m, 2H), 2.10 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.C(=O)([O-])[O-].[K+].[K+].[F:23][CH2:24][CH2:25][CH2:26]I>C(#N)C.O>[F:23][CH2:24][CH2:25][CH2:26][N:13]1[CH2:14][CH2:15][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Reactant: FCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cccc(N2CCN(CCCF)CC2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 1-(3-nitro-phenyl)-piperazine; hydrochloride (1.0 g, 4.1 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in acetonitrile (10 mL) was added 1-fluoro-3-iodo-propane (0.85 g, 4.5 mmol) and was stirred at room temperature for 3 days. The mixture was poured into water (50 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL), dried over magnesium sulfate, filtered and evaporated. 1-(3-Fluoro-propyl)-4-(3-nitro-phenyl)-piperazine was isolated as a viscous orange oil (0.886 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.71 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.18 (dd, J=8.3, 1.9 Hz, 1H), 4.54 (ddd, J=47.2, 5.9, 5.9 Hz, 2H), 3.32-3.27 (m, 4H), 2.65-2.60 (m, 4H), 2.55 (t, J=7.2 Hz, 2H), 2.00-1.85 (m, 2H). MS=268 (MH)+.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]1([S:12]([CH2:15][C:16]([CH3:30])([CH3:29])[CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]([F:28])([F:27])[F:26])[CH2:21][CH2:20]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CI>O1CCCC1>[C:6]1([S:12]([CH:15]([CH3:1])[C:16]([CH3:30])([CH3:29])[CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][CH:22]([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:24]2)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [Li]CCCC
Reactant: CC(C)(CCN1CCC(C(F)(F)F)CC1)CS(=O)(=O)c1ccccc1
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(C)(C)CCN1CCC(C(F)(F)F)CC1)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium (1.5M, 0.13 ml, 0.2 mmol) in hexanes was added to a stirred solution of 1-(4-benzenesulfonyl-3,3-dimethyl-butyl)-4-trifluoromethylpiperidine (40 mg, 0.11 mmol) in tetrahydrofuran (2 ml) at −78° C. The mixture was stirred for 30 min. and methyl iodide (0.34 ml) was added. After 1 hour, the reaction mixture was quenched with one drop of water and concentrated in vacuo. The residue was purified on silica gel (dichloromethane:methanol) to give 1-(4-benzenesulfonyl-3,3-dimethyl-pentyl)-4-trifluoromethyl-piperidine. The title product was prepared by treatment of the amine with 1M ethereal HCl.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[N:25]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[N:26]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:29]1[N:25]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[N:26]=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccc2c(cc(-c3ccnn3C3CCCCO3)n2Cc2ccccc2)n1
Temperature: 25 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.088 g, 0.27 mmol, from Step 2), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.084 g, 0.30 mmol, Aldrich) and Na2CO3 (0.14 g, 1.4 mmol) in 1,2-dimethoxyethane (3 mL) and water (0.5 mL) was degassed by a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.027 mmol, Strem) was added, the vial was capped and heated to reflux for 15 minutes. After cooling to room temperature, the mixture was partitioned between 10% sodium thiosulfate solution and EtOAc. The aqueous layer was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with 25% EtOAc in hexanes afforded product. Yield: (75 mg, 68%).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[CH3:2].S(Cl)([Cl:21])=O>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:21])=[O:13])=[CH:10][CH:9]=1)[CH2:17][CH3:18])[CH3:2]
Reactant: CCN(CC)CCCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)CCCOc1ccc(C(=O)Cl)cc1

Procedure:
A solution of the compound from Example 2(ii)(6 g, 24 mmol) in DCM was stirred at 0° C. Thionyl chloride was added drop-wise and the reaction was heated at reflux for 24 hrs. The reaction was allowed to cool and the solvents removed under vacuum to afford the expected compound as a pungent crude solid. 5.9 g, 100%. The solid was used without further purification.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([C:16](=[C:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH3:17])[CH:13]=[CH:14][CH:15]=2)=[N:7][CH:8]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH:21]1[CH2:22][CH2:23][C:18](=[C:16]([C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=2)[O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:8][N:7]=2)[CH3:17])[CH2:19][CH2:20]1
Reactant: CC(=C1CCN(C(=O)OC(C)(C)C)CC1)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=C1CCNCC1)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 4-(1-(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)ethylidene)piperidine-1-carboxylate (265 mg, 0.591 mmol) in CH2Cl2 (8 mL) was added TFA (2 mL). The reaction was stirred at RT overnight and concentrated to give an oil. This was redissolved in CH2Cl2 and concentrated to give the title compound as an oil (275 mg, 97% yield).
Reaction SMILES: CS(O[C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][O:25][CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[CH2:7]1)(=O)=O.[C:42]([SH:45])(=[O:44])[CH3:43].[H-].[Na+].O>CN(C)C=O>[C:42]([S:45][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][O:25][CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[CH2:7]1)(=[O:44])[CH3:43]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCCNC(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(=O)S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)S[C@H]1C[C@@H](COCCNC(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
A solution of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl]pyrrolidine (0.90 g) in dimethylformamide (2 ml) was added to a reaction mixture of thioacetic S-acid (0.16 ml) and sodium hydride (62.8% in oil suspension) (0.07 g) in dimethylformamide (9 ml) in a nitrogen stream and the mixture was heated at 70°-75° C. for 6 hours. The mixture was poured into water (100 ml), extracted with ethyl acetate (50 ml×2), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with chloroform to give (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl]pyrrolidine (0.60 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[OH-:20].[Na+].Cl>COCCOC>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([OH:20])[N:3]=1
Reactant: [OH-]
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: Nc1nc(O)nc2nc(-c3ccco3)nn12
Reaction time: 2 h

Procedure:
A stirred suspension of 7-amino-2-(2-furyl)-5-methylsulphonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazine (1.4 g) in 1,2-dimethoxyethane (25 ml) was treated with an aqueous solution of 1M sodium hydroxide (25 ml). After 3 hours at room temperature the reaction mixture was acidified with 1M hydrochloric acid (pH 2-3) and stirred for 2 hours. The precipitated yellow solid was collected by filtration and washed with water. Crystallisation from boiling distilled water gave 7-amino-2-(2-furyl)-5-hydroxy-1,2,4-triazolo[1,5-a][1,3,5]triazine (0.47 g) as a pale yellow solid m.p. >300° C.; microanalysis, found: C,44.3; H,2.5; N,38.7%, C8H6N6O2 requires: C,44.0; H,2.8; N,38.5%; NMR: 6.69(dd,1H, furyl-4H), 7.10(d,1H, furyl-3H), 7.90(d,1H, furyl-5H), 8.36(br s, 2H, NH2) and 12.1(br s, 1H,OH); m/e 219 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[CH:22]([CH3:26])[C:23]([OH:25])=[O:24].CCN(CC)CC>ClCCCl>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][N:17]([CH:22]([CH3:26])[C:23]([OH:25])=[O:24])[CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C1N(c2ccc(C3CC3)cc2)CCC12CCNCC2
Reactant: CC(Br)C(=O)O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C(=O)O)N1CCC2(CCN(c3ccc(C4CC4)cc3)C2=O)CC1
Temperature: 80 °C
Yield: 19.5 %

Procedure:
A mixture of 200 mg (0.74 mmol) 2-(4-Cyclopropyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, 168 mg (1.11 mmol) 2-bromo-propionic acid and 224 mg (2.21 mmol) NEt3 in 5 mL DCE was heated to 80° C. for 2 h and concentrated. The residue was taken up in methanol and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 49.4 mg (19%) of the title compound. MS m/e: 343.2 [M+H]+.
Reaction SMILES: Cl.[CH:2]1([CH2:8][NH:9][C:10]([C:12]2([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][CH:20]=3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(OC([NH:35][C@@H:36]([CH2:40][C:41]1[S:42][CH:43]=[CH:44][CH:45]=1)[C:37](O)=[O:38])=O)(C)(C)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:2]1([CH2:8][NH:9][C:10]([C:12]2([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][CH:20]=3)[CH2:13][CH2:14][N:15]([C:37](=[O:38])[C@@H:36]([NH2:35])[CH2:40][C:41]3[S:42][CH:43]=[CH:44][CH:45]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NC(=O)c1ccc(CC2(C(=O)NCC3CCCCC3)CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(CC2(C(=O)NCC3CCCCC3)CCN(C(=O)[C@@H](N)Cc3cccs3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-carbamoylbenzyl)-piperidine-4-carboxylic acid cyclohexylmethylamide hydrochloride (0.584 mmol; 0.23 g) in DMF (5 mL) was added (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (0.642 mmol; 0.174 g), N,N-diisopropyl-N-ethylamine (2.335 mmol; 0.413 mL) and HBTU (0.701 mmol; 0.266 g), and the resulting mixture was stirred at room temperature overnight. The mixture was then purified via reverse phase HPLC and the desired fractions were combined and lyophilized. The resulting residue was dissolved in THF (5 mL) and a 4N HCl solution in 1,4-dioxane (10 mL) was added. The resulting solution was stirred for 5 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 1-(2-(S)-amino-3-thiophen-2-yl-propionyl)-4-(4-carbamoylbenzyl)-piperidine-4-carboxylic acid cyclohexylmethylamide as a hydrochloride salt.