Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:74][CH2:75][CH2:76][CH2:77][N:78]1[CH:82]=[CH:81][N:80]=[CH:79]1>CN(C=O)C>[N:78]1([CH2:77][CH2:76][CH2:75][NH:74][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([NH:8][C:9](=[O:21])[C:10]4[CH:15]=[CH:14][N:13]=[C:12]([N:16]5[CH2:17][CH2:18][CH2:19][CH2:20]5)[CH:11]=4)[CH:4]=3)=[CH:27][CH:26]=2)=[O:30])[CH:82]=[CH:81][N:80]=[CH:79]1
Reactant: NCCCn1ccnc1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)NCCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.6 %

Procedure:
2′-Methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylic acid (40 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), HOBT (13 mg, 0.1 mmol), DIPEA (52 μl), and 1-(3-aminopropyl)imidazole (15 mg, 0.12 mmol) were mixed in DMF (1 ml) and stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the residue partitioned between DCM (5 ml) and aqueous sodium carbonate (1M, 5 ml). The organic phase was applied to a silica gel flash column and eluted with toluene/methanol (8:2), which after evaporation of the solvents under vacuum gave N-{4′-[(3-imidazol-1-ylpropylamino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide (12 mg, 24%). NMR; δH [2H6]-DMSO 10.31,(1H, s), 8.60,(1H, t), 8.19,(1H, d), 7.93,(2H, d), 7.71,(1H, dd), 7.67,(2H, m), 7.45,(2H, d), 7.30,(1H, d), 7.22,(1H, s), 1.93,(6H, m). LCMS: retention time 2.24 min, MH+509.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:10](=O)([O-])[O-].[K+].[K+].ClC[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]>CS(C)=O>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: OCCCCCCCl
Reactant: COc1ccc(O)cc1
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(OCCCCCCO)cc1

Procedure:
A mixture of 4-methoxyphenol (8.7 g), potassium carbonate (9.7 g), 6-chlorohexanol (9.55 g) and DMSO (80 ml) is heated at 120° for 18 hr. Most all of the DMSO is removed at reduced pressure and the residue distributed between ether (400 ml) and water (400 ml). The ether phase is washed with water, saline, dried over sodium sulfate and the solvent removed at reduced pressure to give a residue which is crystallized from ether to give the title compound, m.p. 63°-64°; MS (m/e) 224 (M+).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](OC)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)O>>[OH:2][C:1]1[CH:8]=[CH:7][C:6]2[C:9](=[O:17])[C:10]3[C:11]([O:5][C:4]=2[CH:3]=1)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: COC(=O)c1ccccc1O
Reactant: Oc1cccc(O)c1
Product: O=c1c2ccccc2oc2cc(O)ccc12
Yield: 12.3 %

Procedure:
Resorcinol (5.5 g, 50 mmol) and methyl salicylate (11.0 g, 72 mmol) were refluxed for 5 h using a Dean-Stark trap to remove H2O and MeOH. The resulting black oil was chromatographed over silica with 20% ethyl acetate-hexane as eluent. A yellow solid was isolated which was subsequently recrystallized from ethyl acetate to give 1.3 g (12.3%) of 3-hydroxy-9H-xanthen-9-one (lit. mp 242° C.). Literature references to the synthesis of this compound: R. J. Patolia and K. N. Trivedi, Indian J. Chem., 22B, 444 (1983); J. S. H. Davies, F. Scheinmann, and H. Suschitzky, J. Org. Chem., 23, 307 (1958). ##STR33##
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]\[C:27]([CH2:38][CH3:39])([O:30][Si](CC)(CC)CC)[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([O:47][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]\[C:27]([CH2:38][CH3:39])([OH:30])[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([OH:47])[CH2:10]1
Reactant: CCC(/C=C\CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(/C=C\CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)CC
Yield: 98 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{(Z)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)}pregna-5,7,16-triene (82.0 mg, 0.103 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5.5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate: ethanol=20:80:1, developed once) to give the title compound as a white solid (46.1 mg, 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)=[N:16][N:17]=2)[C:5]([O:11][CH3:12])=[C:6]([CH2:8][CH:9]=O)[CH:7]=1.[NH:32]1[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:19]=3)=[N:16][N:17]=2)[C:5]([O:11][CH3:12])=[C:6]([CH2:8][CH2:9][N:32]2[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]2)[CH:7]=1
Reactant: COc1c(CC=O)cc(F)cc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Reactant: O=C(O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COc1c(CCN2CC(C(=O)O)C2)cc(F)cc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.1 %

Procedure:
To a solution of [5-fluoro-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(methyloxy)phenyl]acetaldehyde (D35) (90 mg) and 3-azetidinecarboxylic acid (80 mg) in dichloromethane (DCM) (20 mL) stirred at room temperature was added AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (84 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA/THF/MeCN for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated. The residue was purified by Mass Directed AutoPrep to give 1-{2-[5-fluoro-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(methyloxy)phenyl]ethyl}-3-azetidinecarboxylic acid (E14) (45 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.34 (6H, d), 2.69 (4H, m), 3.17 (3H, m), 3.41 (2H, m), 3.79 (3H, s), 4.94 (1H, m), 7.43 (1H, dd), 7.52 (1H, d), 7.88 (1H, dd), 8.27 (2H, m). δF (DMSO-d6, 376 MHz): −117.2, −61.3. MS (ES): C25H25F4N3O4S requires 539. found 540.1 (M+H+).
Reaction SMILES: [C:1]([Cl:4])(=O)C.[NH2:5][C:6]1([C:11]([OH:13])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1>CO>[ClH:4].[CH3:1][O:12][C:11](=[O:13])[C:6]1([CH2:10][CH2:9][CH2:8][CH2:7]1)[NH2:5]
Reactant: CC(=O)Cl
Reactant: NC1(C(=O)O)CCCC1
Solvent: CO
Product: COC(=O)C1(N)CCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (1 mL) was added to a cooled solution of methanol (10 mL) and the solution was allowed to warm to room temperature. Cycloleucine (Aldrich; 0.3 g, 2.3 mmol) was added and the solution was allowed to stir overnight at room temperature. The solvent was then evaporated to give cycloleucine methyl ester hydrochloride as an off-white solid which was then combined with 5-(biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (of Intermediate 8; 0.085 g, 0.29 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (Avocado; 0.128 g, 0.67 mmol), and N,N-dimethylaminopyridine (0.16 g, 1.3 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 16 h. The solvents were evaporated under reduced pressure, and water and ethyl acetate were added. The aqueous phase was extracted three times with ethyl acetate, and the combined organic layers were dried (sodium sulfate), filtered, evaporated, and purified using a Biotage Flash 40 purification system, eluting with methylene chloride/acetone 9:1, to give 1-{[5-(biphenyl-4-yloxymethyl)-furan-2-carbonyl]-amino}-cyclopentanecarboxylic acid methyl ester as a colorless oil (0.085 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[CH2:16]([C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)[CH3:17]>O1CCCC1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]([NH:13][S:10]([C:20]2[NH:19][C:18]([CH2:16][CH3:17])=[CH:22][CH:21]=2)(=[O:12])=[O:11])=[O:15])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCc1ccc[nH]1
Solvent: C1CCOC1
Product: CCc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)[nH]1
Temperature: -78 °C
Reaction time: 1 h
Yield: 5.5 %

Procedure:
4-Chloroaniline (4.5 g, 35.4 mmole) was combined with tetrahydrofuran (80 ml) under nitrogen and cooled to -78° C. Chlorosulfonyl isocyanate (3.0 ml, 35.4 mmole) was added and the mixture stirred 1 hour at -78° C. 2-Ethylpyrrole (3.66 g, 38.9 mmole) was added and the mixture allowed to warm to room temperature and then stirred for 2 hours. The reaction was quenched with water and then concentrated. The residue was dissolved in methylene chloride (100 ml) which was extracted with three 100 ml portions of aqueous NaOH. The aqueous layer was acidifed and extracted with methylene chloride. The organic layers were combined and washed with two 100 ml portions of water. The organic layer was then dried over Na2SO4, filtered and concentrated. The resulting dark oil was flashed chromatographed over silica eluding with 4% methanol/methylene chloride. Removal of solvent provided 0.64 g of product.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16]([C:27]4[CH:28]=[C:29]([CH:33]=[O:34])[CH:30]=[N:31][CH:32]=4)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[O:24]1[CH2:23][CH2:22][N:21]([C:18]2[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]4)=[CH:13][C:14]=3[N:15]=[C:16]([C:27]3[CH:28]=[C:29]([CH2:33][OH:34])[CH:30]=[N:31][CH:32]=3)[N:17]=2)[CH2:26][CH2:25]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cncc(C=O)c4)nc(N4CCOCC4)c3s2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cncc(CO)c4)nc(N4CCOCC4)c3s2)CC1
Temperature: 40 °C
Yield: 74.7 %

Procedure:
To 60 mg of 5-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-pyridine-3-carbaldehyde 241 (Example 158) in dry DMF was added sodium triacetoxyborohydride (66 mg) and the reaction mixture was heated at 40° C. overnight. After the SCX-2 cartridge work-up, purification on silica and recrystallization from DCM/hexane gave 235 (45 mg). NMR (CDCl3): 1.80-1.90 (1H, br, OH), 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H, m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 4.86 (2H, s), 7.35 (1H, s), 8.70 (1H, s), 8.71 (1H, s), 9.56 (1H, s). MS (ESI+): MH+ 505.17 (100%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:43])[CH2:32][N:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][O:41]C)[CH2:35][CH2:34]4)[CH:25]=3)=[CH:22][C:15]=2[N:14]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:43])[CH2:32][N:33]4[CH2:34][CH2:35][N:36]([CH2:39][CH2:40][OH:41])[CH2:37][CH2:38]4)[CH:25]=3)=[CH:22][C:15]=2[N:14]=1
Reactant: COCCN1CCN(CC(=O)Nc2cc(Oc3ccc4c(c3)nc(Nc3cc(C(F)(F)F)ccc3F)n4C)ccn2)CC1
Solvent: ClCCl
Product: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(Oc3ccnc(NC(=O)CN4CCN(CCO)CC4)c3)ccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-methoxyethyl)piperazin-1-yl]acetamide (1 eq) in methylene chloride at 78° C. was added 1M borontribromide in methylene chloride (Oeq) and the resulting mixture was stirred at −78° C. for 1 h. It was then brought to ambient temperature and stirred for 2 h. LC/MS showed formation of the product. The reaction was quenched with saturated sodium carbonate solution at 0° C. The mixture was concentrated and then brought to pH=9. It was then extracted with ethyl acetate and the organic layer was dried with sodium sulfate and concentrated and purified on preparative chromatography to yield N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide. MS: MH+=588.6.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[CH:9][N:10]([C@@H:11]3[CH2:15][C@@H:14](O)[CH:13]=[CH:12]3)[C:6]=2[C:5]([F:17])=[CH:4][N:3]=1.CCN(S(F)(F)[F:24])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:17][C:5]1[C:6]2[N:10]([C@@H:11]3[CH2:15][C@H:14]([F:24])[CH:13]=[CH:12]3)[CH:9]=[N:8][C:7]=2[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Nc1ncc(F)c2c1ncn2[C@H]1C=C[C@H](O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ncc(F)c2c1ncn2[C@H]1C=C[C@@H](F)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(1R,4R)-4-(4-amino-7-fluoro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-2-enol (4-3) (600 mg, 2.6 mmol, 1 eq) was dissolved in DCM (120 mL). The mixture was cooled to 0° C. and DAST (1.6 mL, 12.0 mmol, 4.7 eq) was added. The resulting mixture was stirred at the same temperature for 1 hour. Upon disappearance of starting material, the reaction mixture was poured over NaHCO3 (30 mL) and extracted with CHCl3 (3×50 mL). The combined organics were dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (0-100% Acetone in DCM) to afford 7-fluoro-1-((1R,4S)-4-fluorocyclopent-2-enyl)-1H-imidazo[4,5-c]pyridin-4-amine (4-5) as a white solid. LRMS m/z (M+H) 236.9.0 found, 237.1 required.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16](Cl)=[O:17])[CH:13]=[CH2:14].O1CCCC1>C(N(CC)CC)C>[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[N:8]1)=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCCS(=O)(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)CCC)n1

Procedure:
A mixture of 5.25 g. 3-propylsulphonyl-1,2,4-triazole, 5.3 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 1.5 hours. The reaction mixture was worked up as described in Example 1 to give a solid product which was recrystallized from petroleum ether (b.p. 60° - 80° C.) to give 1-diallylcarbamoyl-3-propylsulphonyl-1,2,4-triazole, m.p. 41° - 42° C. Elemental analysis satisfactory.
Reaction SMILES: [NH2:1][C:2]1([C:11]#[N:12])[CH2:7][CH2:6][N:5]([N:8]([CH3:10])[CH3:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[CH2:29][C:30](Cl)=[O:31].C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.O1CCCC1>[C:11]([C:2]1([NH:1][C:30](=[O:31])[CH2:29][C:22]2[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][C:23]=2[CH3:28])[CH2:3][CH2:4][N:5]([N:8]([CH3:9])[CH3:10])[CH2:6][CH2:7]1)#[N:12]
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: CN(C)N1CCC(N)(C#N)CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)c(CC(=O)NC2(C#N)CCN(N(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
920 mg 4-Amino-1-dimethylamino-piperidine-4-carbonitrile (from Step 1), 1.38 g triethylamine and 10 mg N,N-Dimethyl-4-aminopyridine are dissolved in 35 ml tetrahydrofuran. The mixture is cooled in an ice bath and a solution of 1.07 g (2,4,6-trimethyl-phenyl)-acetyl chloride in 15 ml tetrahydrofuran is added. The temperature is kept around 3° C. during addition. Then the mixture is allowed to warm to room temperature and stirred for 2 hours. Then saturated aqueous sodium bicarbonate is added, the mixture is extracted with t-butyl methyl ether, dried over sodium sulfate, and the solvent evaporated. Thus, 1.44 g N-(4-Cyano-1-dimethylamino-piperidin-4-yl)-2-(2,4,6-trimethyl-phenyl)-acetamide is obtained as an off-white solid. 1H-NMR (CDCl3): 6.90 ppm (s, 2H), 5.20 ppm (s, 1H), 3.60 ppm (s, 2H), 2.70 ppm (m, 4H), 2.36 ppm (m, 2H), 2.33 ppm (s, 6H), 2.28 ppm (s, 3H), 2.23 ppm (s, 6H), 1.72 ppm (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]4[C@@H:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][NH:21][CH2:20]4)[CH2:14][CH2:13]3)[C:9]2=[O:30])=[CH:5][CH:4]=1.[CH:33]([O:36][C:37]([Cl:39])=[O:38])([CH3:35])[CH3:34].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[ClH:39].[CH:33]([O:36][C:37]([N:21]1[CH2:22][C@H:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:19]([CH2:18][N:15]2[CH2:16][CH2:17][C:10]3([C:9](=[O:30])[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:32][CH:31]=4)[CH2:12][CH2:11]3)[CH2:13][CH2:14]2)[CH2:20]1)=[O:38])([CH3:35])[CH3:34]
Reactant: CC(C)OC(=O)Cl
Reactant: COc1ccc(CN2CCC3(CCN(C[C@H]4CNC[C@@H]4c4ccccc4)CC3)C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CCC3(CCN(C[C@H]4CN(C(=O)OC(C)C)C[C@@H]4c4ccccc4)CC3)C2=O)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of 2-(4-methoxy-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one (60 μmol) in anhydrous DCM (1 mL) was added isopropylchloroformate (180 μL, 1M in toluene, 180 μmol) and triethylamine (29 μL, 55 μmol). The reaction mixture was stirred overnight at room temperature. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and the aqueous layer washed with dichloromethane (3×2 mL). The organic layer was then concentrated in vacuo and purified by semi-preparative HPLC (Method D) and lyophilized to give the Compound 183 as a colorless solid (15.3 mg, 50%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([NH:25][NH:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)(C)C.CN(C(ON1N=N[C:45]2[CH:46]=CC=N[C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:45]([N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:28]1[C:27]([NH:26][NH:25][C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]=1)=[O:34])([CH3:46])[CH3:44]
Reactant: CC(C)NNC(=O)c1ccccn1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1C=CC=CC1C(=O)NNC(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200 mg, 0.696 mmol), N′-isopropyl picolino hydrazide (187.14 mg, 1.04 mmol) and HATU (397.02 mg, 1.04 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA)(0.1819 ml, 1.04 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4 filtered, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=3:1) dried so that the ivory (E)-tert-butyl 3-(3-(1-isopropyl-2-picolinoyl hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (108.1 mg, 34.6%).
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][C:20]2[N:21]([CH3:25])[N:22]=[CH:23][N:24]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)CCC>O1CCOCC1.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.[Cu]I>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:6]1[N:5]2[N:4]=[C:3]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)[C:2]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[C:10]2[CH:9]=[N:8][N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccccn1
Temperature: 100 °C
Yield: 76.8 %

Procedure:
A mixture of 3-bromo-7-(2-fluorophenyl)-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine (81.8 mg, 0.202 mmol) and 2-(tributylstannyl)pyridine (0.1520 g, 0.413 mmol) in anhydrous 1,4-dioxane (8 ml) was degassed using three freeze-pump-thaw cycles. Tetrakis(triphenylphosphine)palladium(0) (32.5 mg, 0.0281 mmol) and copper(I) iodide (4.5 mg, 0.024 mmol) were added and the mixture was further degassed with one freeze-pump-thaw cycle before heating at 100° C. under nitrogen for 18 h. The mixture was filtered through glass fibre paper, washing well with ethyl acetate (25 ml). The filtrate was washed with saturated aqueous NaCl (10 ml), and the aqueous layer was further extracted with ethyl acetate (25 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified bar flash chromatography (silica gel, 4% MeOH/CH2Cl2 and silica gel, 0-4% MeOH/EtOAc) to give 62.4 mg (77%) of the title compound as a white solid, mp=186-187° C. (CH2Cl2-EtOAc); 1H NMR (400 MHz, CDCl3) δ 3.79 (3H, s), 5.61 (2H, s), 7.20 (1H, m), 7.29 (1H, t, J=9.4 Hz), 7.40 (1H, td, J=7.6 and 0.8 Hz), 7.64 (1H, mn), 7.73 (1H, td, J=7.8 and 1.8 Hz), 7.80 (1H, m), 7.89 (1H, s), 7.94 (1H, d, J=8.0 Hz), 8.70 (1H, m), 10.30 (1H, s); MS (ES+) m/e 403 [MH]+. Anal. Found C, 59.76; H, 3.65; N, 27.65%. C20H15FN8O requires C, 59.70; H, 3.76; N, 27.85%.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[N+:5](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-:6]>ClC(Cl)Cl>[CH2:11]([O:10][C:8]([C:7]1[NH:5][N:6]=[C:2]([CH2:1][OH:4])[CH:3]=1)=[O:9])[CH3:12]
Reactant: C#CCO
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(CO)n[nH]1

Procedure:
A solution of 2 g Prop-2-yn-1-ol and 3 g Ethyl diazoacetate in 16 ml trichloromethane was stirred at 70° C. for 24 h. Then the solvent was removed under reduced pressure and the residue was purified on silica gel eluting with a gradient n-heptane/ethyl acetate 1:1->1:2. The fractions containing the product were collected and evaporated under reduced pressure.