Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18][N:17]([CH3:19])[NH:16][N:15]=2)=[CH:10][CH:9]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:18][N:17]([CH3:19])[NH:16][N:15]=3)=[CH:10][CH:9]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CN1NN=C(c2ccc(Br)cc2)N1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN1NN=C(c2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)N1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
Tris(dibenzylideneacetone)dipalladium (30 mg; 0.03 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (62 mg; 0.10 mmol), sodium tert-butoxide (240 mg; 2.50 mmol), 5-(4-bromo-phenyl)-1-methyl-1H-tetrazole (406 mg; 1.70 mmol, prepared in accordance with Example 18) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (421 mg; 2.1 mmol) are suspended in dry toluene (7 mL) and the mixture is irradiated in a mono-mode microwave oven for 20 min. at 120° C. The mixture is then cooled down to room temperature, is diluted with ethyl acetate (15 mL), is filtered and is concentrated under reduced pressure. The crude residue is finally purified by chromatography on silica gel (dichloromethane:methanol 100:0 to 98:2) to afford the desired product (401 mg; 1.12 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20](O)=[O:21])=[CH:11]2)=[CH:7][C:6]([C:23]([F:26])([F:25])[F:24])=[CH:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:52][C@@H:53]([CH3:56])[CH2:54][NH2:55].C(N(CC)CC)C>CN1C(=O)CCC1.O>[F:52][C@@H:53]([CH3:56])[CH2:54][NH:55][C:20]([C:12]1[C:13]2=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=[C:18]2[N:10]([CH2:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([C:23]([F:24])([F:25])[F:26])[CH:7]=2)[CH:11]=1)=[O:21]
Reactant: C[C@H](F)CN
Reactant: COc1ncc(C(F)(F)F)cc1Cn1cc(C(=O)O)c2ncc(C)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COc1ncc(C(F)(F)F)cc1Cn1cc(C(=O)NC[C@H](C)F)c2ncc(C)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
See FIG. 21(b). In a 25 mL thermal vial was charged with 1-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.27 mmol) and HATU (125 mg, 0.33 mmol) were taken in NMP (4 mL) and stirred for 10 min at rt. Then (S)-2-fluoropropan-1-amine hydrochloride (37.3 mg. 0.33 mmol) and triethyl amine (0.114 mL, 0.82 mmol) were added and stirred for 1 h at RT. The LCMS showed completion of the reaction. The reaction mixture was poured into water and extracted with chloroform. The organic layer was dried and concentrated and crude was submitted to reverse phase purification. The pure fractions were concentrated to get (S)—N-(2-fluoropropyl)-1-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (82 mg, 70.6%) a solid. ES+MS m/z: 425 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.15-1.44 (m, 3 H ) 2.44 (s, 3 H ) 3.39-3.79 (m, 2 H ) 3.98 (s, 3 H ) 4.75 (td, J=6.50, 3.39 Hz, 1 H ) 4.92 (td, J=6.50, 3.20 Hz, 1 H ) 5.48 (s, 2 H ) 7.81 (d, J=2.26 Hz, 1 H ) 7.91-8.03 (m, 1H) 8.25 (s, 1 H ) 8.34-8.42 (m, 1 H ) 8.53-8.62 (m, 1 H ) 8.90 (t, J=5.93 Hz, 1 H ).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([F:18])([F:17])[F:16])=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29]2[C:32]([C:35](O)=[O:36])=[N:33][NH:34][C:28]=2[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([F:18])([F:16])[F:17])=[C:7]([CH:9]2[CH2:10][CH2:11][N:12]([C:35]([C:32]3[C:29]4[CH2:30][CH2:31][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27][C:28]=4[NH:34][N:33]=3)=[O:36])[CH2:13][CH2:14]2)[CH:8]=1
Reactant: Fc1ccc(C(F)(F)F)c(C2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)O)n[nH]c2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cc(F)ccc4C(F)(F)F)CC3)n[nH]c2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidine hydrochloride (11, 93 mg, 0.33 mmol), 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (88 mg, 0.33 mmol), and diisopropylethylamine (0.17 mL, 0.99 mmol) in DMF (6.0 mL) was added EDCI (76 mg, 0.40 mmol) and HOBt (54 mg, 0.40 mmol). The resulting solution was stirred at ambient temperature for 24 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with a saturated brine solution (4×20 mL) and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 5% MeOH in CH2Cl2 with 0.1% NH4OH in CH2Cl2) to provide tert-butyl 3-(4-(5-fluoro-2-(trifluoromethyl)phenyl) piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (43) as a white film (110 mg, 67%): 1H NMR (300 MHz, DMSO-d6) δ 13.16-12.76 (m, 1H), 7.82-7.71 (m, 1H), 7.62-7.50 (m, 1H), 7.33-7.18 (m, 1H), 4.92-4.76 (m, 1H), 4.74-4.59 (m, 1H), 4.53-4.39 (m, 2H), 3.54 (t, J=5.7 Hz, 2H), 3.21-3.01 (m, 2H), 2.86-2.69 (m, 1H), 2.66-2.53 (m, 2H), 1.83-1.62 (m, 4H), 1.42 (s, 9H); ESI MS m/z 497 [M+H]+.
Reaction SMILES: Cl.N[C:3]1[O:4][C:5]2[C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][C:15]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([OH:29])(C)C>>[C:22]([C:15]1[CH:16]=[C:17]([C:18]([CH3:21])([CH3:19])[CH3:20])[C:5]2[O:4][C:3](=[O:29])[CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:6]=2[CH:14]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)O
Reactant: CC(C)(C)c1cc(C(C)(C)C)c2oc(N)c(-c3ccccc3)c2c1
Agent: Cl
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
4.8 ml (9.58 mmol) of 2N HCl is added at room temperature to a solution of 3.08 g (9.58 mmol) of 2-amino-3-phenyl-5,7-di-tert-butyl-benzofurane [compound (301), Table 3, prepared according to Example 1a] in 10 ml iso-propanol and stirred at room temperature for 90 minutes. The precipitate is filtered and washed with isopropanol. Crystallization of the residue from isopropanol yields 2.62 g (85%) of 5,7-di-tert-butyl-3-phenyl-3H-benzofuran-2-one (compound (101), Table 1), m.p. 116-119° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19]C)=[CH:17][CH:18]=2)=[CH:4][N:3]=1.[Si](I)(C)(C)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(Cc2cnc(Cl)c3ccccc23)cn1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Cc2cnc(Cl)c3ccccc23)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Under exclusion of moisture, to 500 mg (1.76 mmol) of 1-chloro-4-[(6-methoxy-pyridin-3-yl)methyl]-isoquinoline (step 28.6) in 9 ml of chloroform, 488 μl (3.58 mmol) of Me3SiI are added. Then the mixture is stirred for 8 h at 60° C. Dilution of the mixture with EtOAc and NaHCO3-solution, stirring and filtration of the suspension yields 1-chloro-4-[(6-hydroxy-pyridin-3-yl)methyl]-isoquinoline, contaminated with 1-iodo-4-[(6-hydroxy-pyridin-3-yl)methyl]-isoquinoline; FAB-MS: (M+H)+=271chloride/363iodide; HPLC(gradient20-100) tRef=10.2chloride/10.8iodide. From the filtrate, more product can be obtained by extraction with EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[CH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15]C)=[O:14])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[CH:9]\[C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C=C(Cn2ccnc2)c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(/C=C(/Cn2ccnc2)c2ccc(F)cc2)c1
Yield: 73.1 %

Procedure:
A solution of the product from step B (E and Z isomers) (11 g , 32.7 mmol) in MeOH (150 ml) was treated with 2N NaOH (32 ml, 65 mmol) for 3 hours. Methanol was then evaporated and the solution was acidified to pH 5.5 with 6N HCl. The resulting precipitate was filtered and washed with a small quantity of water. The precipitate was taken up in MeOH. The insoluble material was washed with a mixture of MeOH/ether to give after drying 2.3 g of E isomer 3-((E)-2-(4-fluorophenyl)-3-(imidazol-1-yl)-prop-1-enyl)benzoic acid (22%). The above filtrate was evaporated and triturated in ether to give the E isomer 3-((E)-2-(4-fluorophenyl)-3-(imidazol-1-yl)-prop-1-enyl)benzoic acid (7.7 g, 67%) as a solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:11][CH:12]1[O:17][CH2:16][CH2:15]C[O:13]1>>[O:17]1[CH:16]=[CH:15][O:13][CH:12]1[CH2:11][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: BrCC1OCCCO1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)CC(=O)CCC1OC=CO1

Procedure:
The title compound was synthesized from ethyl acetoacetate and 2-bromomethyl-1,3-dioxane, according to the procedure of Huckin and Weiler, Tetrahedron Lett. 3927, (1971).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[Cu](C#N)[C:14]#[N:15]>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: N#C[Cu]C#N
Reactant: COc1cc(Cl)c(I)nc1OC
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(C#N)nc1OC
Temperature: 150 °C

Procedure:
To a solution of 3-chloro-2-iodo-5,6-dimethoxypyridine (1-6c, 230 mg, 0.768 mmol) in DMF (7.7 mL) was added copper cyanide (138 mg, 1.54 mmol) and heated to 150° C. for 20 minutes in a microwave reactor. The mixture was partitioned between water and EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to yield the desired product (1-6d) as a bone-colored crystalline powder. ESI+ MS [M+H]+ C8H8ClN2O2=198.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:27][C:28]#[CH:29].CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:16][O:17][CH2:29][C:28]#[CH:27])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C#CCCl
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc(C)cc2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOC=C(C(=O)NCCc1ccc(OC)c(OC)c1)c1ccc(C)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
Five hundred miligrams (500 mg) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(4-methylphenyl)acrylamide (1.47 mmol), 0.11 g (1.47 mmol) of 3-chloropropyne and 5 ml of anhydrous N,N-dimethylformamide were mixed and 64 mg (1.61 mmol) of 60% sodium hydride was added thereto at 0-5° C. The mixture was stirred at 0-10° C. for 30 minutes and then stirred at room temperature. Water was added to the reaction mixture, followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=1:1) to give 180 mg of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-(2-propynyloxy)-2-(4-methylphenyl)acrylamide (the present compound 1182).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.CCCCCC>C(OCC)(=O)C>[CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:32]=3)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Reactant: COc1cccc(B(O)O)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cccc(-c2ccc3c(c2)C2(CCCCC2)C(=NOCc2ccccc2)N3)c1
Yield: 73.1 %

Procedure:
Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime) (1.0 g, 2.6 mmol) and 3-methoxyphenyl boronic acid (0.79 g, 5.2 mmol) according to Example 45 procedure A. The product was purified by flash silica gel chromatography; (eluant: 10:0.5 hexane:ethyl acetate) to give the desired product (0.80 g, 1.9 mmol, 75%) as a viscous oil. 1H NMR (500 MHz, DMSO-d6) δ 1.43-1.78 (8H, m), 1.95-2.00 (2H, q), 3.80 (3H, s), 5.00 (2H, s), 6.82-6.86 (2H, m), 7.10-7.16 (2H, m), 7.28-7.53 (10H, m), 9.57 (1H, s); MS (ESI(−ve)) m/z 411 (M−H)−.
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.N1C=CN=C1.CCN(CC)CC.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl.O>[Si:21]([O:7][CH:4]1[CH2:5][CH2:6][CH:1]([OH:8])[CH2:2][CH2:3]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a solution of 1,4-cyclohexanediol (5 g, 43 mmol), imidazole (2.92 g, 43 mmol) and NEt3 (7 mL) in CH2Cl2 (100 mL) cooled in an ice bath was added tert-butyldimethylsilyl chloride (6.47 g, 43 mmol). The mixture was stirred at room temperature overnight. Water was added and the organic phase was separated. The aqueous layer was extracted with EtOAc. The combined organic phase was dried over MgSO4 and concentrated. Chromatography on silica gel eluting with 3:1 EtOAc/hexanes provided the title compound (4.2 g, 42%) as an oil. MS calculated (M+H)+ 231. found 231.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[N:5][C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3]1.[C:14](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=1)#[CH:14]
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(N2CCCC2)nc1C=O
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1nc(N2CCCC2)nn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To a stirred mixture of 1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (1.57 g, 8.71 mmol, Eq: 1.00) and potassium carbonate (2.41 g, 17.4 mmol, Eq: 2) at 25° C. in methanol (60 ml) under an argon atmosphere was added dropwise a solution of dimethyl 1-diazo-2-oxopropylphosphonate (2.01 g, 1.57 ml, 10.5 mmol, Eq: 1.2) in methanol (12 ml). The mixture was stirred at 25° C. for 3 h. The crude material was applied on silica gel and purified by flash chromatography over a 50 g silica gel column using dichloromethane/methanol 0-10% as eluent affording 5-ethynyl-1-methyl-3-pyrrolidin-1-yl-1H-[1,2,4]triazole (785 mg, 51.1%) as an orange solid. MS: m/z=149.2 (M+H+)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([F:14])[CH:12]=2)[NH:7][CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17].O.[NH4+].[OH-]>C(O)C>[F:14][C:11]1[CH:12]=[C:13]2[C:5]([C:3]3[N:15]=[C:16]([NH2:18])[S:17][CH:2]=3)=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1c[nH]c2ncc(F)cc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2c[nH]c3ncc(F)cc23)cs1
Temperature: 70 °C
Yield: 82.3 %

Procedure:
Aluminum chloride (0.48 g, 3.6 mmol) was added slowly to a stirred solution of 5-fluoro-1H-pyrrolo[2,3-b]pyridine (0.164 g, 1.2 mmol) in CH2Cl2 (5 mL)). Bromoacetyl bromide (0.1 mL, 1.5 mmol) was added and the resulting solution was heated at 50° C. for 1 h and cooled to room temperature. Water (25 mL) was added, the solution was basified with saturated NaHCO3 and the mixture was extracted with EtOAc (3×25 mL). The organic extracts were dried and concentrated under reduced pressure to give 2-bromo-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone as a pale brown solid. A mixture of 2-bromo-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (0.28 g) and thiourea (0.13 g) in ethanol (10 mL) were heated at 70° C. for 1 h. Water (50 mL) was added and the solution was basified with concentrated NH4OH. The aqueous layer was extracted with EtOAc (3×25 mL). The organic extracts were dried and concentrated under reduced pressure to give 4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-amine (0.21 g, 75%, 2 steps) as pale brown solid. Mass Spec.; MS 235 (M+1); 1H NMR(DMSO-d6, 500 MHz) δ 11.86(s, 1H), 8.27(d, 1H), 8.22(s,1H), 7.83(d,1H), 6.95(brs,2H), 6.81(s,1H).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([N:7]2[C:11]3=[C:12]4[S:18][CH:17]=[CH:16][C:13]4=[N:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@H:19]([OH:21])[CH3:20])[CH2:3]1.C(N(CC)C(C)C)(C)C.[C:31](#[N:35])[CH2:32][CH2:33][CH3:34]>C(#N)C>[OH:21][C@@H:19]([C:8]1[N:7]([C@H:4]2[CH2:5][CH2:6][N:2]([CH2:34][CH2:33][CH2:32][C:31]#[N:35])[CH2:3]2)[C:11]2=[C:12]3[S:18][CH:17]=[CH:16][C:13]3=[N:14][CH:15]=[C:10]2[N:9]=1)[CH3:20]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCNC1
Reactant: CCCC#N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCN(CCCC#N)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
To a mixture of (1R)-1-{1-[(3S)-pyrrolidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol hydrochloride (15 mg, 0.046 mmol) and N,N-diisopropylethylamine (24 μL, 0.14 mmol) in acetonitrile (0.2 mL) was added butanenitrile, 4-bromo- (5.1 μL, 0.051 mmol). The resulting mixture was stirred at rt for 4 h. The mixture was diluted and purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 6.3 mg (38%) of the desired product. LCMS calculated for C18H22N5OS (M+H)+: m/z=356.2. Found: 356.0.
Reaction SMILES: [F:1][C:2]([F:23])([Cu])[C:3]([F:21])([F:20])[C:4]([F:19])([F:18])[C:5]([F:17])([F:16])[C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].[CH2:24](Br)[C:25]#[CH:26]>>[F:1][C:2]([F:23])([CH:24]=[C:25]=[CH2:26])[C:3]([F:21])([F:20])[C:4]([F:19])([F:18])[C:5]([F:17])([F:16])[C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[Cu]
Reactant: C#CCBr
Product: C=C=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 10 %

Procedure:
L. Coe and N. E. Milner, Journal of Organometallic Chemistry, 70, 147(1974) disclosed the reaction of perfluoro-n-heptyl copper with propargyl bromide at 110° C. to be an extremely violent exothermic reaction that afforded, after a difficult workup that included a minor explosion, a 10% yield of 1-(perfluoro-n-heptyl)-1,2-propadiene. There is no disclosure nor suggestion relating to a means of performing said conversion in a safe, controllable, reproducible, high-yield manner.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[C:4]([C:9]([F:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[F:13][C:3]1[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][CH:10]=[C:9]([F:12])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1c(F)ccc(N)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(F)ccc(NS(C)(=O)=O)c1F
Reaction time: 24 h

Procedure:
To a solution of methyl 3-amino-2,6-difluorobenzoate (530 mg, 2.83 mmol) and pyridine (0.28 mL, 3.40 mmol) in 10 mL CH2Cl2 was added methanesulfonyl chloride (0.24 mL, 3.11 mmol). After 24 h at room temperature, the reaction mixture was washed with saturated aqueous NaHCO3 and extracted with CHCl3 to provide crude methyl 2,6-difluoro-3-[(methylsulfonyl)amino]benzoate as a solid (ESI-MS 264 (M−H)), which was hydrolyzed using aqueous NaOH to provide 2,6-difluoro-3-[(methylsulfonyl)amino]benzoic acid (ESI-MS 250 (M−H)), which was used without further purification.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=[O:21])[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.Cl.N1C=CN=C1.[C:32]([Si:36]([CH3:39])([CH3:38])Cl)([CH3:35])([CH3:34])[CH3:33].O>CN(C)C=O.C(OCC)C>[Si:36]([O:25][C:3]1[CH:2]=[CH:1][C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C:5]=2[C:4]=1[O:19][C@H:18]4[C:20](=[O:21])[CH2:22][CH2:23][C@@:9]35[OH:24])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:39])[CH3:38]
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 76 %

Procedure:
3.49 g of naltrexone hydrochloride was suspended in 10.5 ml of N,N-dimethylformamide. After adding 3.46 g of imidazole, 3.48 g of tert-butyldimethylchlorosilane was added followed by stirring for 35 minutes at room temperature. 30 ml of water and 50 ml of diethyl ether were added to the reaction system followed by separation. The aqueous layer was extracted twice with 30 ml of diethyl ether. The combined extracts were dried over anhydrous sodium sulfate and concentrated. The resulting residue was recrystallized from ethanol to obtain 3.2 g of the target compound (yield: 76%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([S:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]>CC#N>[CH:27]([O:26][C:24]([N:13]1[CH2:14][CH2:15][CH:10]([S:9][C:6]2[C:7]([CH3:8])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=2)[CH2:11][CH2:12]1)=[O:25])([CH3:29])[CH3:28]
Reactant: Cc1c(Cl)ncnc1SC1CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(Cl)ncnc1SC1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
A mixture of 4-chloro-5-methyl-6-(piperidin-4-ylsulfanyl)-pyrimidine (HCl salt, 1.8985 g, 6.77 mmol) and triethylamine (2.825 mL, 0.02 mol) in 50 mL of CH3CN was stirred under room temperature. After 15 min, isopropyl chloroformate (1M in toluene, 8.13 mL, 8.13 mmol) were added slowly under 0° C. Mixture was stirred under room temperature. After 3 h, mixture was concentrated and residue was extracted with EtOAc and saturated NaHCO3. Organic phase was dried over MgSO4, filtered and concentrated to give 4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylic acid isopropyl ester as yellowish oil (1.9143 g, 85%). Exact mass calculated for C14H20ClN3O2S 329.1, found 330.3 (MH+).