Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[N:13][C:12]([C@@H:15]2[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][CH3:22])[CH2:16]2)=[CH:11][N:10]=1)(OC(C)(C)C)=O.Cl>C(Cl)Cl>[CH3:22][O:21][C@H:17]1[CH2:18][CH2:19][CH2:20][C@@H:15]([C:12]2[N:13]=[CH:14][C:9]([NH2:8])=[N:10][CH:11]=2)[CH2:16]1
Reactant: CO[C@H]1CCC[C@@H](c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cn2)C1
Agent: Cl
Solvent: ClCCl
Product: CO[C@H]1CCC[C@@H](c2cnc(N)cn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(+/−)-N,N-di-Boc-5-((1R,3S)-3-methoxycyclohexyl)pyrazin-2-amine (184 mg, 0.452 mmol) in DCM (4. 515 mL) was added HCl (4M in dioxane) (4.515 mL, 18.06 mmol). The reaction mixture was stirred at room temperature overnight. After the volatile material was removed in vacuo, the residue was dissolved in EtOAc. The organic layer was washed by NaHCO3 solution, water and brine, dried over anhydrous Na2SO4, and concentrated affording (+/−)-5-((1R,3S)-3-methoxycyclohexyl)pyrazin-2-amine in quantitative yield. LCMS (m/z): 208 (MH+), 0.43 min. To a solution of (+/−)-5-((1R,3S)-3-methoxycyclohexyl)pyrazin-2-amine (54 mg, 0.261 mmol) in acetonitrile (4. 008 μL) was added NBS (48.7 mg, 0.274 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. After quenched with NaHCO3, extracted with EtOAc three times. The organic layer was washed by water and brine, dried over anhydrous Na2SO4, and concentrated to afford 75 mg of (+/−)-3-bromo-5-((1R,3S)-3-methoxycyclohexyl)pyrazin-2-amine in quantitative yield. LCMS (m/z): 286 (MH+), 0.73 min.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:21]([NH:20][CH2:19][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=3)=[O:22])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc2c(N)cccc12
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: Cc1nccc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc12

Procedure:
Prepared from 1-methylisoquinolin-5-amine (Description 68) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 360 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([O:30][N:31]=C(C)C)[CH:23]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl>CCO>[CH3:20][C:19]1[CH:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][C@H:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]2[CH2:21][C:22]2[CH:29]=[CH:28][C:25]3[C:26]([NH2:27])=[N:31][O:30][C:24]=3[CH:23]=2)[NH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)=NOc1cc(CN2[C@@H](c3ncccc3C)CCC[C@H]2c2ncccc2C)ccc1C#N
Agent: Cl
Solvent: CCO
Product: CC1=CC=CNC1[C@@H]1CCC[C@H](c2ncccc2C)N1Cc1ccc2c(N)noc2c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
To a solution of 4-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-2-isopropylideneaminooxy-benzonitrile (0.145 g, 0.320 mmol) in EtOH (4 mL) was added aqueous HCl (3 N, 4 mL), and the mixture was stirred and heated at reflux overnight. The mixture was then cooled to room temperature, EtOH was removed, and saturated aqueous NaHCO3 (20 mL) was added. The aqueous mixture was extracted with CH2Cl2 (4×40 mL), and the combined extract was dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified on silica gel column (100:5:2 CH2Cl2/CH3OH/NH4OH), affording 6-((2′S,6′R)-3,3″-dimethyl-3′, 4′, 5′, 6′-tetrahydro-2H-2,2′;6′,2″-terpyridin-1′-ylmethyl)-1,2-benzisoxazol-3-ylamine as a white solid (0.082 g, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:19])([F:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:18])([F:19])/[CH:16]=[CH:17]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccccc1
Reactant: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(Br)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(F)(F)/C=C/c1ccccc1

Procedure:
Prepared according to the procedure described in Example 124, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-difluoro-but-3-en-1-ol and iodobenzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12]([C:14]([O:17]C(=O)C)([CH3:16])[CH3:15])=[O:13])[NH:7][C:6](=[O:21])[CH2:5]2.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12](=[O:13])[C:14]([OH:17])([CH3:16])[CH3:15])[NH:7][C:6](=[O:21])[CH2:5]2
Reactant: CC(=O)OC(C)(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: 25 °C
Yield: 51.7 %

Procedure:
Acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-1-methyl-ethyl ester 11a (2.035 mg, 6.9 mmol) was dissolved in 20 mL of methanol under stirring at room temperature, and 20 mL of sodium hydroxide solution (0.7 M) was then added to the solution. The reaction solution was stirred for 4 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the above solution was neutralized with hydrochloric acid (1 M) and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dried to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide 11b (900 mg, yield 59.2%) as a white solid.
Reaction SMILES: C[NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:20]=2)[CH:4]=1.BrC1C=C(C2C=C(N)N=C(C3C=CC=CN=3)C=2)C=NC=1>>[NH:29]1[CH2:28][CH2:27][CH:26]([N:24]2[CH:25]=[C:21]([C:19]3[CH:20]=[C:15]([C:5]4[CH:4]=[C:3]([NH2:2])[N:8]=[C:7]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=5)[CH:6]=4)[CH:16]=[N:17][CH:18]=3)[CH:22]=[N:23]2)[CH2:31][CH2:30]1
Reactant: CNc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccccn2)n1
Agent: Nc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Product: Nc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccccn2)n1

Procedure:
This compound is prepared analogously to methyl-[5″-(1-piperidin-4-yl-1H-pyrazol-4-yl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.183) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step1) with 5″-Bromo-[2,2′;4′,3″]terpyridin-6′-ylamine (Example 1.31).
Reaction SMILES: C(P([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])CC)C.CC(C)([O-])C.[K+].[CH2:18]([C@H:23]1[CH2:28][CH2:27][C@H:26]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH:35]=O)[CH2:31][CH2:30]2)[CH2:25][CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22].O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:18]([C@H:23]1[CH2:28][CH2:27][C@H:26]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH:35]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:31][CH2:30]2)[CH2:25][CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)CP(CC)CC
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=CC(=O)OCC)CC2)CC1
Temperature: -5 °C

Procedure:
In a 1-L three-neck flask equipped with a stirrer, a thermometer and a dropping funnel, 27.6 g (122.9 mmol) of ethyl diethylphosphinoacetate was dissolved in 350 ml of IRAQ tetrahydrofuran (hereinafter abbreviated as THF) under nitrogen atmosphere and the solution was cooled down to −5° C. while stirring. 15.2 g (135.2 mmol) of potassium t-butoxide was added thereto, and the solution was stirred at room temperature for 2 hours. The solution was cooled down again to 0° C., and a solution of 25.0 g (94.5 mmol) of trans-4-(trans-4-pentylcyclohexyl)cyclohexanecarbaldehyde dissolved in 100 ml of THF was added dropwise. Further, the solution was stirred at room temperature for 14 hours, and then 200 ml of water and 400 ml of toluene were added to the reaction mixture and stirred. The separated toluene layer was washed twice with 200 ml of water and dried over anhydrous magnesium sulfate, and then toluene was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography with toluene used as a developing solvent to obtain 12.8 g of ethyl 3-(trans-4-(trans-4-pentylcyclohexyl)cyclohexyl)propenoate (yellow oily substance).
Reaction SMILES: C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCCCC)(=O)C1C=CC=CC=1.[C:26]([C:34]1[C:42]([N+:43]([O-])=O)=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=1[O:46][CH2:47][CH:48]([CH3:50])[CH3:49])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:43][C:42]1[C:34]([C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:35]([O:46][CH2:47][CH:48]([CH3:50])[CH3:49])[CH:36]=[C:37]([CH:41]=1)[C:38]([OH:40])=[O:39]
Reactant: CC(C)COc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Agent: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: CC(C)COc1cc(C(=O)O)cc(N)c1C(=O)c1ccccc1

Procedure:
By replacing in Example 1, step C, 4-benzoyl-3-n-butoxy-5-nitrobenzoic acid with 4-benzoyl-3-isobutoxy-5-nitrobenzoic acid, and following the procedure described, 5-amino-4-benzoyl-3-isobutoxybenzoic acid is obtained with a melting point of 192°-196° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)(=[O:12])=[O:11].C([O-])(=O)C.[K+].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][CH2:34][C:35]2[NH:44][C:38]3=[N:39][CH:40]=[C:41](I)[CH:42]=[C:37]3[N:36]=2)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][CH2:34][C:35]2[NH:44][C:38]3=[N:39][CH:40]=[C:41]([C:16]4[CH:17]=[CH:18][C:13]([S:10]([NH:9][C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])(=[O:12])=[O:11])=[CH:14][CH:15]=4)[CH:42]=[C:37]3[N:36]=2)[CH:28]=1
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)Nc5ccccc5OC)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 27.8 %

Procedure:
A mixture of 0.513 g of N-(2-methoxyphenyl)-4-bromo-benzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 17 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 19 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 28-20:1). Concentration of the chromatographically pure fractions and crystallisation from ethylacetate gives 0.14 g of the title compound as a solid of m.p. 215-216° C. The mass spectrum shows the molecular peak MH+ at 516.3 Da.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:24]=[N:25][C:26]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][C:28]=2[O:29][CH3:30])=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.C[O-].[Na+]>CO>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[CH:24]=[N:25][C:26]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][C:28]=1[O:29][CH3:30])[C:17](=[O:19])[CH:16]=[CH:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cnc(-c2cccc(F)c2)cc1OC
Agent: CCCCP(CCCC)CCCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2cccc(F)c2)ncc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Reaction time: 2 h
Yield: 33.3 %

Procedure:
A MeOH solution of (E)-ethyl 3-(5-(benzylthio)-2-((6-(3-fluorophenyl)-4-methoxypyridin-3-yl)amino)phenyl)acrylate (0.615 g, 1.195 mmol) and tributylphosphine (0.060 ml, 0.239 mmol) in a 40-mL vial was stirred overnight at 70° C. Sodium methoxide, 25 wt % solution in methanol (0.106 ml, 0.478 mmol) was then added. After stirring for 2 h, the reaction was concentrated under a stream of N2 and purified via column chromatography (50 g Snap Ultra column, 0% to 100% EtOAc/hept) to afford 6-(benzylthio)-1-(6-(3-fluorophenyl)-4-methoxypyridin-3-yl)quinolin-2(1H)-one (186.7 mg, 0.398 mmol, 33.3% yield) as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.92 (s, 3 H) 4.26 (s, 2 H) 6.60 (d, J=8.81 Hz, 1 H) 6.72 (d, J=9.53 Hz, 1 H) 7.20-7.39 (m, 6 H) 7.42 (dd, J=8.81, 2.18 Hz, 1 H) 7.61 (dd, J=8.03, 1.92 Hz, 1 H) 7.83 (d, J=2.18 Hz, 1H) 7.90 (s, 1H) 8.00 (d, J=9.43 Hz, 1 H) 8.04-8.09 (m, 1 H) 8.09-8.13 (m, 1 H) 8.45 (s, 1 H). m/z (ESI) 469.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=3)[N:25](S(C3C=CC=CC=3)(=O)=O)[CH:24]=2)[CH:3]=1.[OH-].[Na+].C(O)(C(F)(F)F)=O>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=3)[NH:25][CH:24]=2)[CH:3]=1
Reactant: CCOc1cnc2c(c1)c(-c1cc(Cl)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c1)cn2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cnc2[nH]cc(-c3cc(Cl)nc(N[C@H]4CC[C@H](N)CC4)c3)c2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of Example 224b (76.1 mg, 0.122 mmol) in dioxane (1.5 mL) was treated with 20% sodium hydroxide (0.10 mL, 0.122 mmol). The mixture was heated at 90° C. for 1 hour. The solvent was evaporated. The residue was treated with 20% brine and extracted with EtOAc (2×). The combined organic layers were dried. The crude intermediate was dissolved in CH2Cl2 (1.0 mL) and treated with TFA (0.19 mL, 2.4 mmol). After 1 hour, the reaction mixture was concentrated and purified by reverse-phase HPLC as described in Example 56 to give the title compound (6.5 mg) as trifluoroacetic acid salts. 1H NMR (400 MHz, CD3OD) ppm 1.29-1.43 (m, 2H), 1.43-1.49 (m, 3H), 1.52-1.72 (m, 2H), 2.02-2.17 (m, 2H), 2.17-2.32 (m, 2H), 3.13 (m, 1H), 3.80 (m, 1H), 4.18 (q, J=7.02 Hz, 2H), 6.75 (d, J=1.22 Hz, 1H), 6.86 (d, J=1.22 Hz, 1H), 7.86 (s, 1H), 7.90 (d, J=2.44 Hz, 1H), 8.06 (d, J=2.44 Hz, 1H). MS (DCI+) m/z 386.2 (M+H)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:13]([C@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:24][N:23]([C:10](=[O:12])[CH2:9][S:8][C:5]2[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=2)[C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)CSc1ccncc1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CSc1ccncc1
Yield: 12.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(pyridin-4-ylthio)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 96, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(pyridin-4-ylthio)acetyl)pyrrolidine-2-carboxamide (4 mg, 12.3%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.97 (s, 1H), 8.34 (d, 2H), 7.55 (m, 2H), 7.33-7.28 (m, 5H), 7.25-7.18 (m, 6H), 6.95 (m, 2H), 4.49 (m, 1H), 4.14 (m, 2H), 3.86 (m, 1H), 3.56 (m, 1H), 2.69 (m, 3H), 1.95 (m, 2H). MS (EI) for C31H28FN3O3S. found 542.6 (MH+).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[S:19][C:17]=2[N:18]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4-dichloro-6-nitro-thieno-[2,3-d]-pyrimidine gives 2-chloro-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:11](/[N:15]=[CH:4]/[C:3]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN
Reactant: O=Cc1c(F)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC/N=C/c1c(F)cccc1Cl
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of 59.8 g (377 mmol) 2-chloro-6-fluorobenzaldehyde in 250 ml toluene were added 41.0 ml (415 mmol) N-butylamine and 1.44 g (7.54 mmol) p-toluenesulphonic acid. The mixture was heated at reflux for 5 h. After cooling to room temperature, the mixture was diluted with toluene and washed sequentially with aqueous sodium bicarbonate solution, water and saturated brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford 80.1 g (99% of the title compound as a dark brown oil which was used in the next step without further purification. MS (ISP): 216.2 ([{37Cl}M+H]+), 214.2 ([{35Cl}M+H]+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([P:10]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)([CH2:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH3:9].Cl[C:23]1[N:31]=[C:30]([I:32])[N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>C1COCC1>[CH2:7]([P:10]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:23]2[N:31]=[C:30]([I:32])[N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[CH:19][CH:20]=1)([CH2:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH3:9]
Reactant: CCCP(=O)(CCC)c1ccc(N)cc1
Reactant: Clc1nc(I)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCP(=O)(CCC)c1ccc(Nc2nc(I)nc3c2ncn3C2CCCCO2)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-Butoxide (0.19 g, 1.65 mmol) was suspended in 4.5 mL anhydrous THF under nitrogen and cooled to −10° C. in an ice-salt bath. 4-(Dipropylphosphoryl)benzenamine (0.12 g, 0.55 mmol) was added to the suspension and the mixture was stirred at −10° C. for 30 min. 6-Chloro-2-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Tetrahedron 2002, 58, 7911-7923, 0.18 mg, 0.5 mmol) was then added to the reaction mixture and the content was warmed to room temperature and stirred over night. The reaction mixture was cooled to 0° C., and quenched by the addition of 0.1 N HCl (˜500 mL). The mixture was concentrated on a rotavapor. The residue was partitioned between ethyl acetate (10 mL)/water (4 mL), organic layer was separated and washed with 0.1 N HCl (4×4 mL), saturated NaHCO3 (4 mL), brine (4 mL), and dried over Na2SO4. The final product was obtained by flash column chromatography on silica gel (7.5% MeOH/DCM).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]#[N:22])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])=[C:4]([CH3:23])[CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[NH:26][N:25]=[N:24][N:22]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])=[C:4]([CH3:23])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(Cl)ccc1-c1nc(C#N)sc1-c1ccc(Cl)cc1C
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Product: Cc1cc(Cl)ccc1-c1nc(-c2nnn[nH]2)sc1-c1ccc(Cl)cc1C
Temperature: 150 °C
Yield: 71 %

Procedure:
A round-bottomed flask was charged with 4,5-bis(4-chloro-2-methylphenyl)thiazole-2-carbonitrile (150 mg, 0.42 mmol), zinc bromide (189 mg, 0.84 mmol) and sodium azide (45.5 mg, 0.84 mmol). After degassed, DMF (3 mL) was added. The reaction mixture was heated to 150° C. overnight. After cooled to rt, the reaction was quenched with 30 mL of 0.1 N aqueous HCl, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (hexane:EtOAc:AcOH=30:10:1). 120 mg of product was obtained as a white solid, 1H NMR (DMSO, 500 MHz) δ 7.93 (d, J=8.41 Hz, 1H), 7.57 (d, J=1.90 Hz, 1H), 7.49-7.44 (m, 2H), 7.33-7.28 (m, 2H), 2.63 (s, 3H), 2.18 (s, 3H); 13C NMR (DMSO, 125 MHz) δ 166.07, 153.61, 139.50, 138.74, 134.92, 133.48, 132.53, 131.87, 131.42, 130.27, 129.98, 126.64, 125.67, 21.13, 19.51.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:22][CH3:23])=[CH:11][C:12]([C:20]#[N:21])=[C:13]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])[CH:14]=1)C1C=CC=CC=1.FC(F)(F)C([O-])=O>FC(F)(F)C(O)=O>[C:20]([C:12]1[CH:11]=[C:10]([O:22][CH3:23])[C:9]([OH:8])=[CH:14][C:13]=1[N:15]=[CH:16][N:17]([CH3:18])[CH3:19])#[N:21]
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)c(N=CN(C)C)cc1O
Yield: 143.5 %

Procedure:
N′-(5-(benzyloxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (110 g, 356 mmol) and trifluoroacetic acid (600 ml) were heated at reflux for 15 minutes. The reaction was evaporated in vacuo and then azeotroped with toluene. The residue was triturated with diethyl ether and the solid collected by suction filtration. The solid was dried in vacuo to yield N′-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide (112 g, 95% yield) as a light brown trifluoroacetate salt:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[CH:19]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]1)=[O:15])=O)(C)(C)C>Cl.C(OCC)(=O)C>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[CH:19]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]1)=[O:15]
Reactant: COC(=O)CC1CCN(C(=O)NCCCCNC(=O)OC(C)(C)C)Cc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CC1CCN(C(=O)NCCCCN)Cc2ccccc21

Procedure:
Methyl 2-(2-(N-(4-tertbutoxycarbonylaminobut-1-yl) carbamoyl)-1H,3H,4H-5H-benzo[e]azapin-5-yl)acetate was stirred in HCl in ethyl acetate (1.17M, 20 mL) at room temperature for 12 h. The solvent was removed under vacuum and the residue was trituated with ether. The product was diluted with methylene chloride and extracted with sodium hydroxide (0.5M). The organic phase was concentrated in vacuo and azeotroped with toluene to yield the product as a white solid. EI-MS m/z 334 (M+H)+