Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1C2C=CC=CC=2N=C1CN(C1C2N=CC=CC=2CCC1)CC1C=CC(CN)=CC=1.C([O:35][C:36]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40](O)=O)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:1][CH2:40][CH:39]1[CH2:43][CH2:44][CH2:45][NH:38][C:36]1=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NCC1CCCNC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 451.3 %

Procedure:
To a stirred solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (148 mg, 0.37 mmol) in dry CH2Cl2 (5 mL) was added N-(tert-butoxycarbonyl)-L-proline (88 mg, 0.41 mmol), N,N-diisopropylethylamine (0.13 mL, 0.75 mmol), 1-hydroxybenzotriazole hydrate (68 mg, 0.50 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (EDC) (99 mg, 0.52 mmol) and the mixture stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (25 mL) and saturated aqueous sodium bicarbonate (30 mL) and the aqueous layer was separated and extracted with CH2Cl2 (2×15 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give the crude product as a white foam. Purification by column chromatography on silica gel (CH2Cl2/MeOH, 96:4) gave the desired amide (214 mg, 85%) as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si](C)(C)C)=[CH:12][CH:11]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[CH:17])=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)C#Cc1ccc(C(=O)Nc2ccccc2N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1ccc(C(=O)Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
To a stirred solution at −20° C. of a mixture of 198 and 199 in anhydrous THF (15 ml) under nitrogen was added a solution of TBAF (1 ml, 1.0 M in THF). The reaction mixture was allowed to warm up to room temperature over 2 h and stirred at room temperature for 18 h. Then, the reaction mixture was poured into a saturated aqueous solution of NH4Cl and diluted with ethyl acetate. After separation, the organic layer was successively washed with sat. NH4Cl, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/hexane: 30/70) to afford the title compound 199 (215 mg, 0.91 mmol, 46% yield over 2 steps) as a pale yellow powder. 1H NMR (300 MHz acetone-d6) (ppm): 9.19 (bs, 1H), AB system (δA=8.08, δB==7.66, J=8.5 Hz, 4H), 7.33 (d, J=7.6 Hz, 1H), 7.05 (t, J=7.3 Hz, 1H), 6.91 (d, J=7.6 Hz, 1H), 6.72 (t, J=7.6 Hz, 1H), 4.67 (bs, 2H), 3.88 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[OH:4].[C:29]1([C:40](O)=[O:41])[CH:30]=[CH:31][CH:32]=[C:33]2[CH2:39][CH2:38][CH2:37][CH:36]=[CH:35][C:34]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[CH:2]([NH:1][C:40]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[CH2:39][CH2:38][CH2:37][CH:36]=[CH:35][C:34]=12)=[O:41])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (206 mg, 0.53 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (268 mg, 90%).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([S:13](=[O:18])(=[O:17])[N:14]([CH3:16])[CH3:15])[N:8]=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(S)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].N#N>CN(C)C=O>[CH3:15][N:14]([CH3:16])[S:13]([C:9]1[N:8]=[C:7]([N:6]2[C:2]([S:13]([NH2:14])(=[O:18])=[O:17])=[C:3]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:4]=[N:5]2)[CH:12]=[CH:11][CH:10]=1)(=[O:18])=[O:17]
Reactant: CCOC(=O)c1cnn(-c2cccc(S(=O)(=O)N(C)C)n2)c1Cl
Agent: N#N
Agent: O=C([O-])[O-]
Agent: SCc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2cccc(S(=O)(=O)N(C)C)n2)c1S(N)(=O)=O
Yield: 186.3 %

Procedure:
To 50 ml of dried dimethylformamide, added were 4.2 g of ethyl 5-chloro-1-(6-dimethylsulfamoylpyridin-2-yl)pyrazole-4-carboxylate and 1.46 g of benzylmercaptan and 3.2 g of potassium carbonate, followed by stirring at room temperature for 24 hours in the atmosphere of N2. After the reaction, inorganic salt was filtered off and dimethylformamide was evaporated from the filtrate to obtain 4.4 g of the title compound as an oily product.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([O-])(O)=O.[Na+].OP([O-])([O-])=O.[K+].[K+].[O-]S([O-])(=O)=O.[Mg+2].[Br:28]Br>O.C(Cl)Cl.C(Cl)(Cl)Cl>[Br:28][C:3]1[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[S:1][CH:2]=1
Reactant: BrBr
Reactant: c1cc2sccc2cn1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Brc1csc2ccncc12
Yield: 28.5 %

Procedure:
1.46 g of Thieno[3,2-c]pyridine (10.8 mmol), 907 mg of NaHCO3 (10.8 mmol), 2.82 g of K2HPO4 (16.2 mmol) and 1.69 g of MgSO4 (14.04 mmol) are placed into the flask with 40 ml of chloroform. The reaction mixture is stirred under reflux. 0.72 ml of bromine (14.04 mmol) is added slowly to the mixture and kept stirring for overnight. CH2Cl2 and water are added to the cooled reaction mixture and separated CH2Cl2 layer is dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane: AcOEt=5:1→Hexane:AcOEt:2 M NH3 in MeOH=10:3:1) to give 660 mg of the title compound. Yield 29%. mass spectrum (m/e): 215 (M+1); 1H-NMR (CDCl3): 9.17 (m, 1H), 8.59 (m, 1H), 7.83 (d, 1H, J=5.2 Hz), 7.52 (s, 1H) ppm.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:10])=[N:2]1.S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][N:2]=[C:3]([OH:10])[C:4]=2[CH:9]=1)([O-:18])=[O:17]
Reactant: Oc1noc2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2onc(O)c2c1
Reaction time: 1.5 h

Procedure:
1,2-Benzisoxazol-3-ol (19.7 g, 0.146 mol) is added portionwise to concentrated sulfuric acid. The resultant reaction mixture is treated dropwise with 70% nitric acid (11.3 mL), stirred for 90 minutes, and poured onto ice. The resultant aqueous mixture is filtered to obtain a waxy paste. The paste is recrystallized from a methanol/water mixture to give the title product as a solid which is identified by 1H NMR spectral analysis.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[C:15]2[O:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]=2[CH:10]=[C:9]([Br:18])[CH:8]=1)C.O.[OH-].[Li+]>CO.O1CCCC1.O>[Br:18][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:19])=[O:3])[C:15]2[O:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]=2[CH:10]=1
Reactant: CCOC(=O)CCc1cc(Br)cc2c1OCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)COc2c(CCC(=O)O)cc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of 3-(5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-propionic acid ethyl ester (Intermediate 76, 0.875 g, 2.67 mmol) in methanol (15 mL), tetrahydrofuran (15 mL) and water (7 mL) was treated with lithium hydroxide monohydrate (0.68 g, 16 mmol) and the resulting reaction mixture was stirred at room temperature for 1 h. The volatiles were evaporated in vacuo and the residue was diluted with water and washed with diethyl ether. The aqueous phase was neutralized with concentrated hydrochloric acid and the solution was extracted with ether (×3). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to afford the title compound as an oily foam (0.64 g, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(#N)C.O>CCO.C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: O
Solvent: CCO
Solvent: O=CO
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccc(F)cc1
Reaction time: 8 h
Yield: 9.4 %

Procedure:
To a solution of 5-bromopyridin-3-amine (3 g, 17.34 mmol) in absolute EtOH (15 ml), 4-fluorobenzene-1-sulfonyl chloride (0.989 g, 5.08 mmol) was added and the reaction was stirred overnight. Ethanol was removed under reduced pressure and residue was diluted with DCM (40 ml) and washed once with sat. NaHCO3. Organic phase was dried over Na2SO4, filtered and concentrated. Product was straightforward purified via reverse phase chromatography with a Biotage C18 30 g column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (158 mg, 24.4% yield) as yellow pale solid.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:9]=2)=[CH:6][C:5]([CH:34]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH3:35])=[CH:4][N:3]=1.[S:42]1[C:46]2[CH:47]=[CH:48][C:49]([NH2:51])=[CH:50][C:45]=2[N:44]=[CH:43]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>C1COCC1>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:51][C:49]3[CH:48]=[CH:47][C:46]4[S:42][CH:43]=[N:44][C:45]=4[CH:50]=3)=[N:3][CH:4]=[C:5]([CH:34]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[CH3:35])[CH:6]=2)[N:9]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCOCC4)cnc3F)n2)cc1
Reactant: Nc1ccc2scnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cc(C(C)N3CCOCC3)cnc2Nc2ccc3scnc3c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 6.1 %

Procedure:
A mixture of 4-(2-fluoro-5-(1-morpholinoethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.300 g, 0.537 mmol) and benzo[d]thiazol-5-amine (0.202 g, 1.343 mmol) in THF (10 mL) was chilled to 0° C. in an ice bath. Then sodium bis(trimethylsilyl)amide (1.0 M solution in THF, Aldrich; 2.148 mL, 2.148 mmol) was added into the mixture via syringe. After the addition, the ice bath was removed and the mixture was allowed to stir under an inert atmosphere for 1 h. The reaction mixture was diluted with water (30 mL) and the organic layer was extracted with chloroform (3×20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. This gave the crude bis-PMB protected product as a tan oil. This crude material was treated with trifluoroacetic acid (1.8 mL) and trifluoromethanesulfonic acid (0.2 mL). The reaction mixture was placed into a pre-heated bath (70° C.) and allowed to stir under inert atmosphere for 10 min. The mixture was removed from the heat source and allowed to cool to ambient temperature. The mixture was concentrated in vacuo. The crude residue was diluted with DCM (10 mL), and then sodium carbonate (1.5 g) was added to the mixture with stirring. The mixture was filtered and concentrated in vacuo. The crude was purified by reverse phase HPLC (Varian, 5-70% acetonitrile in water with trifluoroacetic acid as additive 0.1% v/v in each solvent) to give N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(1-morpholinoethyl)pyridin-2-yl)benzo[d]thiazol-5-amine (0.015 g, 0.033 mmol, 6.23% yield) as a tan solid. 1H NMR (400 MHz, d6-DMSO) δ 12.24 (s, 1H) 9.36 (s, 1H) 8.92 (s, 1H) 8.75 (s, 1H) 8.36 (s, 1H) 8.06 (d, J=8.61 Hz, 1H) 7.92 (s, 1H) 7.82 (d, J=8.61 Hz, 2H) 3.57 (s, 4H) 3.29-3.46 (m, 1H) 2.50 (d, J=7.82 Hz, 5H) 2.34 (s, 2H) 1.36 (d, J=6.46 Hz, 3H). m/z (ESI, +ve ion) 449.1 (M+H)+.
Reaction SMILES: S1C=CC(C2N3N=C(N)N=C3C=CC=2)=C1.Br[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([N:23]=[C:24]([NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]=2)[CH:22]=1.[OH:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[OH:35][C:36]1[CH:41]=[C:40]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([N:23]=[C:24]([NH:26][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]=3)[CH:22]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1ccccc1
Reactant: OB(O)c1cccc(O)c1
Agent: Nc1nc2cccc(-c3ccsc3)n2n1
Product: O=C(Nc1nc2ccc(-c3cccc(O)c3)cn2n1)c1ccccc1
Yield: 12 %

Procedure:
The title compound was prepared following procedure described for intermediate A1, step a), but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B5), 75 mg; 0.24 mmol; 1.0 eq.) and 3-hydroxyphenylboronic acid (65 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (EtOAc/c-Hex, gradient from 50:50 to 100:0) gave the title compound as a brown solid (9.5 mg, 12%). HPLC, Rt: 2.59 min. (purity 91.6%). LC/MS, M+(ESI): 331.1, M−(ESI): 329.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH2:24])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(C2CCCN(C(=O)OCc3ccccc3)C2)cc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNc1cc(C2CCCN(C(=O)OCc3ccccc3)C2)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.2 %

Procedure:
3-(3-Amino-4-methyl-phenyl)-piperidine-1-carboxylic acid benzyl ester (Example 13; 230 mg, 0.71 mmol) was dissolved in 5 mL dimethylformamide. Cesium carbonate (462 mg, 1.42 mol) and ethyl bromoacetate (86 μL, 0.78 mmol) were added and the mixture stirred at ambient temperature under a nitrogen atmosphere for 72 h. An additional 86 μL of ethyl bromoacetate were added and the reaction stirred an additional 24 h. The mixture was diluted with 100 mL water and extracted with diethyl ether (2×50 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 20% ethyl acetate/hexanes to yield 152 mg (52%) of 3-[3-(ethoxycarbonylmethyl-amino)-4-methyl-phenyl]-piperidine-1-carboxylic acid benzyl ester as a clear oil.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.CO.[OH-].[NH4+]>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a solution of N-tert-butyl-2-(6-methylpyridin-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (55 mg, 121 mol) in dichloromethane (1.9 mL) was added trifluoroacetic acid (276 mg, 186 μL, 2.42 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained then dissolved in dichloromethane (2 mL), methanol (1 mL) and ammonium hydroxide (0.25 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated and triturated with water, then filtered to obtain a solid which was washed with ether and dried to give N-tert-butyl-2-(6-methylpyridin-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33 mg, 102 mol, 84%) as a brown solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.23 (s, 1H), 9.41 (s, 1H), 8.60 (d, J=2.3, 1 H), 7.91 (m, 3H), 7.59 (s, 1H), 7.06 (d, J=8.5, 1 H), 2.31 (s, 3H), 1.32 (s, 9H); MS (EI/CI) m/z: 325.1 [M+H].
Reaction SMILES: Cl[CH2:2][C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[CH2:4].ClCC(C)=CCC=C(C)C.[CH3:21][C:22]([C:29]#[CH:30])=[CH:23][CH2:24][CH2:25][C:26](=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[CH3:21][C:22]([C:29]#[C:30][CH2:2][C:3]([CH3:4])=[CH:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:23][CH2:24][CH2:25][C:26](=[O:28])[CH3:27]
Reactant: C#CC(C)=CCCC(C)=O
Reactant: C=C(CCl)CCC=C(C)C
Agent: CC(C)=CCC=C(C)CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(=O)CCC=C(C)C#CCC(C)=CCC=C(C)C
Yield: 93 %

Procedure:
The coupling reaction was conducted in the manner described in the procedure of Example XVIII using the following reagents: 162 mg (1.02 mmoles) of a mixture of 2-chloromethyl-6-methyl-1,5-heptadiene and 1-chloro-2,6-dimethyl-2,5-heptadiene (produced in accordance with Example XXI), 138 mg (1.01 mmoles) of 6-methyl-5-octen-7-yn-2-one (produced in accordance with Example II), 232 mg (1.68 mmoles) of anhydrous potassium carbonate, 9 mg (0.09 mmole) of cuprous chloride, and 20 mg (0.088 mmole) of benzyltriethylammonium chloride in 1.00 mL of acetonitrile (HPLC-grade). Isolation of the product in the manner described in the procedure of Example III afforded 242 mg (93% yield) of material, shown by proton NMR analysis to contain a minor amount (approximately 25%) of unreacted starting ketone and allylic chlorides. Fractional evaporative distillation afforded 136 mg (52% yield, not corrected for recovery of starting materials) of the named unsaturated C-18 ketones: boiling point 115°-128° C. (bath temperature, 0.20 mm). The identity of this product mixture was confirmed by high-field (300 MHz) proton NMR analysis.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13](=[O:24])[N:14]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[CH:8]=1)(=O)=O.[CH:34]([NH:37][CH2:38][CH2:39][NH2:40])([CH3:36])[CH3:35].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[C:15]2[C:10](=[C:9]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[CH:8]=[C:7]([NH:40][CH2:39][CH2:38][NH:37][CH:34]([CH3:36])[CH3:35])[CH:16]=2)[CH:11]=[CH:12][C:13]1=[O:24]
Reactant: O=c1ccc2c(-c3ccccc3Cl)cc(OS(=O)(=O)C(F)(F)F)cc2n1-c1ccccc1Cl
Reactant: CC(C)NCCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)NCCNc1cc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2c1
Yield: 11.7 %

Procedure:
1,5-bis(2-chlorophenyl)-2-oxo-1,2-dihydro-7-quinolinyl trifluoromethanesulfonate (50 mg, 0.097 mmol), N-isopropylethylenediamine (0.36 ml, 2.885 mmol), racemic BINAP (74 mg, 0.119 mmol), palladium(II) acetate (17 mg, 0.076 mmol), and cesium carbonate (0.14 g, 0.43 mmol) in 1,4-dioxan (4 ml) were heated under reflux under nitrogen for 2 h. The solvent was removed in vacuo, and the residue partitioned between water (8 ml) and dichloromethane (10 ml). The mixture was passed through a hydrophobic frit, and the filtrate passed though two 5 g SCX-2 cartridges, and eluted with methanol followed by 2M ammonia in methanol. The latter fractions were evaporated in vacuo and the residue purified by mass directed autoprep (per general procedure B) to afford the title compound as a gum (5.3 mg, 10%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][NH2:5].[F:7][C:8]([F:15])([F:14])[C:9](OCC)=O>CC1C=CC(C)=CC=1>[F:7][C:8]([F:15])([F:14])[C:9]1[NH:1][CH2:2][CH:3]([OH:6])[CH2:4][N:5]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCC(O)CN
Solvent: Cc1ccc(C)cc1
Product: OC1CN=C(C(F)(F)F)NC1

Procedure:
A solution of 1,3-diaminopropan-2-ol (10.0 g, 111 mmol) and ethyl 2,2,2-trifluoroacetate (15.8 g, 111 mmol) in p-xylene (150 mL) was stirred at 160° C. for 4 h, then concentrated to remove solvent under reduced pressure to afford the crude product as an oil, which was used into next step without purification.
Reaction SMILES: CC(O)=O.Cl[S:6]([C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([CH3:22])[CH:10]=1)(=O)=O.Cl[Si](Cl)(C)C.[F:28][C:29]([F:46])([F:45])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH:42](O)[CH3:43])[CH:37]=2)=[CH:32][CH:31]=1>CCOC(C)=O.[Zn]>[CH3:22][C:11]1[CH:10]=[C:9]([S:6][CH:42]([C:38]2[CH:37]=[C:36]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:45])[F:46])=[CH:31][CH:32]=3)[CH:41]=[CH:40][CH:39]=2)[CH3:43])[CH:21]=[CH:20][C:12]=1[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Agent: C[Si](C)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(SC(C)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
Zinc (229 mg, 3.50 mmol) was added to EtOAc (10 mL) followed by AcOH (115 μM, 2.00 mmol) and ethyl [4-(chlorosulfonyl)-2-methylphenoxy]acetate (293 mg, 1.00 mmol). After 2 hours, dichlorodimethylsilane (258 mg, 2.00 mmol) was added followed by 1-[4′-(trifluoromethyl)-3-biphenylyl]ethanol (266 mg, 1.00 mmol) and the mixture stirred for a further 1 hour and then heated at 80° C. for 5 hours. The mixture was then cooled, diluted with EtOAc and washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl, water and brine, and then reduced. Purification by Biotage™ chromatography (silica) eluting with petrol:EtOAc (9:1) afforded the title compound as a colourless oil (238 mg).